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BioMed Research International
Volume 2013 (2013), Article ID 928562, 21 pages
A Comprehensive Focus on Global Spectrum of BRCA1 and BRCA2 Mutations in Breast Cancer
Department of Medical Genetics, Tehran University of Medical Sciences, School of Medicine, Tehran, Iran
Received 17 April 2013; Revised 31 July 2013; Accepted 15 August 2013
Academic Editor: Ana Maria Tari
Copyright © 2013 Fatemeh Karami and Parvin Mehdipour. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Breast cancer (BC) is the most common cancer of women all over the world. BRCA1 and BRCA2 gene mutations comprise the most important genetic susceptibility of BC. Except for few common mutations, the spectrum of BRCA1 and BRCA2 mutations is heterogeneous in diverse populations. 185AGdel and 5382insC are the most important BRCA1 and BRCA2 alterations which have been encountered in most of the populations. After those Ashkenazi founder mutations, 300T>G also demonstrated sparse frequency in African American and European populations. This review affords quick access to the most frequent alterations among various populations which could be helpful in BRCA screening programs.
Breast cancer (BC) is the most common malignancy in females in almost all of countries with highest age-adjusted incidence in developed countries (73%) and includes the 23% of all types of cancers. World Health Organization (WHO) report shows that this incidence increases 2% per year . The incidence rate in Iranian women is found to be 16.2 per 100,000 people per year which is standardized for age, and the mortality rate is 5.5 per 100,000 people per year . As a matter of fact, BC is responsible for most of deaths due to cancer in women all over the world. According to surveys which were globally conducted, the overall rate of BC is higher in American and European women compared to the Asian, and it may be related to the life style of Asian population . The major type of BC is found to be sporadic with estimated frequency ranging from 90% to 95%, and the rest (5–10%) includes the familial BC . It was demonstrated that BC patients in Iran are usually younger than European or American counterparts given that familial or hereditary BC comprises the main risk factor among Iranian woman.
The most important genes which were proposed for inherited BC as high penetrant genetic susceptibility include BRCA1 and BRCA2, p53, PTEN, STK11/LKB1, and CDH1 genes , while some others like ATM, CHECK2, BRIP1, and PALB2 are considered as moderate genetic factors. BRCA1 and BRCA2 genes will be discussed in detail in the following sections of this paper.
P53 is a known gene involved in Li-Fraumeni cancer syndrome and could be identified in 20%–35% of breast tumors and has about 1400 mutation types which almost involve transactivation domain.
BC shows 4% more risk in women who are carrier of PTEN gene mutations. This gene encodes the phosphatase and tensin homologue and its mutations is often found in ductal carcinoma and triple negative forms of BC. Promoter hypermethylation has been suggested as a probable mechanism of loss of heterozygosity (LOH) in breast tumor . It was described that PTEN loss of function not only is involved in tumor formation but also causes resistance to targeted therapy.
Studies could not find somatic mutation in STK11/LKB1 locus on chromosome 19p which is responsible for Peutz-Jeghers syndrome (PJS) and only the LOH of this tumor suppressor locus was determined in BC samples. It is taught that the aforementioned locus is accompanied by 5 times more risk of BC in PJS patients .
CDH1 gene encodes for E-cadherin which is determined as a primary indicator in addition to estrogen receptor α (ERα) for luminal epithelial tumors of breast . Women who are carriers of CDH1 mutations have 39%–52% to be affected with BC in their life. It was identified that most of the nonsynonymous mutations have impact on three-dimensional structure of this protein . On the other hand, CDH1 underexpression is associated with more metastasis and poor prognosis in either ER positive or negative BCs .
Ataxia telangiectasia-mutated (ATM) gene encodes for ATM protein which is involved in double-stranded breaks DNA repair and regulation of cell cycle. It was shown that being carrier of heterozygote mutations of this gene is associated with increased risk of BC. We have demonstrated the D1853N polymorphism in exon 36 of ATM gene is significantly more frequent in BC patients compared to the external and internal control groups . Based on our proposed three-hit hypothesis, D1853N in conjunction of IVS 38- 63T>A and IVS 38- 30 A>G within ATM gene, comprised the triangle of astrocytoma development in an Iranian proband affected with astrocytoma as well [8, 9].
The greater risk belongs to BRCA1 and BRCA2 genes which enhance the risk of BC progression up to 59%–87% and 38%–80% respectively. BRCA1 gene mutations accounts for 1-2% BC and approximately all of the familial breast-ovary tumors. It seems that BRCA1 and BRCA2 gene mutations are associated with higher grades of breast tumors . BRCA proteins are involved in repair of break in double-strand DNA through homologous recombination and also cell cycle progression. Loss of function in BRCA1 and BRCA2 genes is responsible for male BC . The mutations in both proteins also increase the risk of ovarian and prostate cancers with special risk of pancreatic cancer for BRCA2 and colon cancer for BRCA1 mutations . The BRCA1 and BRCA2 defective tumors demonstrate specific pattern of genetic alterations required for tumor genesis; for example, Myb amplification and p53 mutation with different pattern frequently occur in BRCA1 deficient tumors compared to sporadic ones; this is in contrast to Her2 and cyclin D1 overexpression. In addition, we could often detect the BRCA1 mutations in ER and PR negative BCs, so they have poor response to tamoxifen therapy [12, 13].
2. Structure of BRCA1 and BRCA2 Genes and Proteins
The BC susceptibility gene, BRCA1, is located at chromosome 17q21 and codes for an 1863 amino acid protein involved in gene regulation processes following DNA damage. BRCA2 gene was mapped on chromosome 13q12.3 by positional cloning and translation following its transcription which leads to the formation of a protein with 3,418 amino acids. About 41.5% of BRCA1 gene is unusually composed of Alu sequences versus low density of other repeat sequences (4.8%) .
BRCA1 and BRCA2 genes have 24 and 27 exons, respectively. The largest exon in both genes is exon 11 (3.5 kbp in BRCA1) which harbors the most important and frequent mutations in BC patients. In contrast, one of the noncoding regions of genome is located in exon 1 of both BRCA1 and BRCA2 genes.
The overall structure of BRCA1 protein comprises of zinc finger in amino terminal, C3HC4 type (RING finger) which creates a loop structure through binding two zinc atoms by eight amino acids. In addition, the BRCA1 C Terminus (BRCT) domain, nuclear localization signal, and nuclear export signal motifs could be found within BRCA1 protein structure (Figure 1).
All the proteins containing RING finger have role in ubiquitination pathway as E3 ubiquitin ligase. The Zinc finger structure contains Cys3HisCys4 amino acid motif which is highly conserved and every change in this amino acid composition could affect binding properties of BRCA1 protein. BRCA1 is involved in transcriptional regulation through interaction with histone deacetylase complexes via its BRCT domain. The similar BRCT domain called BRC motif is found in proteins as well as BRCA2 which are participated in cell cycle checkpoint and function in response to DNA damage. It is associated with the area for single-strand binding and a region with 26 amino acids called PhePP motif that binds to DMC1 which is a meiosis-specific recombinase. A domain binding single-stranded DNA containing 3 oligonucleotide-binding (OB1-3) folds and a helix-turn-helix motif that binds double stranded DNA is located in C-terminal segment of BRCA2. Moreover, there is a region in the 3′ end of BRCA2 gene, in exon 11, called ovarian cancer cluster region (OCCR) which may increases the risk of ovarian cancer in BRCA2 families if become mutated [16, 17]. Figure 2 shows the different interaction sites of BRCA2.
BRCA1 combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multisubunit protein complex known as the BRCA1-associated genome surveillance complex (BASC).
BRCA1 and BRCA2 orthologs have been identified in most mammals for which complete genome data are available .
3. BRCA1 and BRCA2 Mutations
Over 2000 different mutations have been reported in BRCA1/2 genes including deletions, insertions, and many single nucleotide substitutions in coding or noncoding sequences. The most common types of mutation are attributed to small insertion/deletion frameshift, nonsynonymous truncation, and disruption of splice site leading to entire nonfunctional BRCA proteins. The higher rate of duplication/deletion in BRCA1 gene versus BRCA2 (42% and 20%, resp.) is due to accumulation of Alu sequences . Large genomic rearrangements (LGRs) comprise about 1/3 of all mutations occurring in BRCA1 gene which are typically a result of homologous recombination between BRCA1 gene and the same pseudogene sequences .
In BRCA2 gene, most of mutations occur in exons 10 and 11 and usually include insertions or deletions which raise the missense alterations and premature stop codon ending in truncated and nonfunctional protein. It was shown that the segments of BRCA2 that were separated out contain double strand break domain (DBD), nuclear localization signal (NLS), and Rad-51 binding motif are located in C-terminal which are critical for BRCA2 function .
All of the most important and frequent BRCA1 and BRCA2 mutations which have been discovered so far are represented in Tables 2, 3, 4, 5, 6, 7, and 8. Some of the BRCA1/2 mutations show population specific pattern and some of them have been found in various studies from different populations.
In this review we are intended to describe the most important polymorphisms at a glance and then the most frequent and important mutations of different populations from all over the world based on the studies which have been freely published online up to April 2013. Finally, we will discuss about the genotype-phenotype correlation of BRCA1/2 gene alterations highlighted in various ethnicity.
4. Polymorphisms and Variants in BRCA1 and BRCA2 Genes at a Glance
There are many reports for different polymorphisms within BRCA1 and BRCA2 genes all over the world. They are classified into four major categories: silent, nonsynonymous, harmful, and unclassified whose impacts on BRCA1/2 genes remain to be clear. In this section, we will take a look at the most important variants discovered in different populations whose promoting or protective role in BC development has been verified (Table 1).
S1613G in exon 16 and P871L accompanying E1038G in exon 11 constitute the most common single nucleotide polymorphisms in BRCA1 gene which were frequently reported in BC family assays of India, Greek, Malay, Sri Lanka, Turkey, and Italy. S1613G is responsible for amino acid switch from serine to glycine which was detected among Italian women who were carriers of the major BRCA1 mutations [21–25]. Other polymorphisms in this gene are E879E, S919P, and Y1137Y. They have been replicated in different populations including Chinese and Finnish. Although the S919P takes place in BACH1 domain, it was not considered as a high predisposal factor of BC .
Among other variants which have been identified in BRCA1, c.1984C.T changes the histidine to tyrosine and disrupts the BRCA1 protein function. So it could be also regarded as a pathogenic variant which was only detected in Cypriot population .
There are also some other variants in BRCA1 which are associated with anomalous splicing and lead to premature translation and truncated protein including c.302-3C>G in BRCA1 and c.475G>A in addition to c.7007G>A in BRCA2. They have been described in a Czech population assay and were considered as deleterious variants . In addition, Y179C in exon 8 of BRCA1 converting a conserved tyrosine was found in several German BC families along with Ashkenazi Jews , one Australian family , and an Italian family . Functional study of BRCA1 protein containing this and some other variants (Y105C, P142H, and E143 K) has identified that proline residue interferes with recognizing double strand break site in DNA and may eventually disturb the participation of BRCA1 protein in DNA repair . Moreover, C5242A (A1708E) polymorphism in exon 18 of BRCA1 gene leads to exchange of alanine to glutamine residues. owing to its occurrence in BRCT domain, it may interrupt the interaction of BRCA1 protein with others especially those being involved in DNA repair. It was discovered in Hispanic BC families from Spain and El Salvador but it substantially comes from western European descent. It is maybe helpful to consider this variant in high risk Hispanic populations .
Furthermore, there is an insertion/deletion mutation in intron 24 (3′ UTR) of BRCA1 gene that belongs to unclassified variants with unknown effect and was found in one of our study families with five BC patients .
There are three variants in BRCA1 gene whose their protective effect against BC has been proposed. Since the lack of K1183R variant in exon 11 of BRCA1 gene in which the two basic amino acids transform to each other (lysine to arginine) increases the risk of BC, it could be considered as another protective polymorphism. The second is RR genotype for Q356R polymorphism which has shown meaningful lower frequency in BC cases relative to controls . Since, the intron variant, IVS7-34T.C has shown 40% more frequency in controls, a defending mechanism could be defined for it against BC in further studies [35, 36].
It was discovered that the 3232A>G base pair exchange was more seen versus 1342A>C mutation in carriers of BRCA1 harmful alterations .
The association of S1832P, T2766I, N2781I, and K2860T polymorphisms in BRCA2 with BC risk was defined in Danish population and it was predicted that they can negatively affect BRCA2 function . Moreover, c.9023A/C introduces a turn in BRCA2 protein structure by replacing the proline with histidine. So this nonsynonymous variant may interfere with normal BRCA2 function in Chilean families .
The c.72A>T (Leu24Phe) has been found in Finnish BC women recently. In silico assessments predicted that it possibly influences the BRCA2 protein in pathogenic ways . Although Miramar et al. described that some variants such as K3083E or 9475A>G introduce a drastic amino acid exchange (lysine to glutamine) and represent functional disturbance in BRCA2 protein , they are still known as a nonpathogenic polymorphism. 4817A>G in exon 11 of BRCA2 gene provides the suitable codon for converting the lysine residue to argenine and was only characterized in Romanian BC study. Given its pathologic effect on BRCA2 protein function, it is regarded as a deleterious polymorphism in screening programs of this population .
Healy et al. have reported that a specific BRCA2 variant (N372H) was associated with increased reproductive fitness in males in the United Kingdom and an increased BC risk in females. Based on the Meta-analysis review on the association of it with BC, it seems that 372H is not meaningfully associated with higher risk of BC in Asian, Caucasian, and African populations. However, further assays including controls samples are required to validate this result .
5. Global Distribution of BRCA1 and BRCA2 Mutations
5.1. Ashkenazi Jews
Ashkenazi Jewish population is one of the well-known population in which the founder mutations including 5382insC, 185delAG in BRCA1, and 6174delT in BRCA2 were detected. These three mutations were also identified in other populations which will be discussed in the following sections. In a study on Ashkenazi Jews residing in USA, the BRCA2 3036del4 mutation was identified in only one BC patient diagnosed <50 yrs and the remainders were positive for the mentioned founder alterations . However, 5382insC founder mutation was not found in Ashkenazi Jews from Brazil maybe due to selection of BC patients without familial history of BC .
5.2. Northern Europe
All the mutations regarding Northern European population were brought in Table 2.
In Finnish BC patients, BRCA2 mutations have been reported more than BRCA1 gene. The novel c.72A>T as destabilizing mutation, c.68-80insT, and c.793 + 34T>G alterations were identified. Except of a large deletion covering the exons 1–13 which were recognized in a family with ovarian cancer, no deletion/duplication has been detected in this population thus far . Moreover, the 4088insA in BRCA2 gene is found to be associated with a better prognosis of Finnish BC women .
Amongst Swedish population affected with BC, two founder mutations in BRCA1 gene including 3172ins5 and 2594delC have been originated from Central Europe. The 1806C>T and 1201del11 alterations comprise the remainder of founders that were replicated in two Swedish assays. It is noteworthy that all of the BRCA1 main alterations are mapped on exon 11. In addition, 4486delG is the most frequent and founder alteration in exon 11 of BRCA2 gene [47, 48].
The major point of BRCA1 and BRCA2 screening in Danish population is that the prevalence of BRCA2 mutations was found to be more frequent in west than in east Denmark. The most important and common alterations of BRCA1 gene include: 2594delC, 5382insC, 3829delT, 3438G>T, 1675delA, and Q563X and for BRCA2 6601delA, 1538del4, 6714del4, and 999del5. Danish population shares some founder mutations with Norwegian and Swedish peoples that could propose a unique ancestry for these three Scandinavian countries [38, 49].
The most frequent mutations of BRCA1 gene which are replicated in multiple Norwegian studies are 1135insA, 1675delA, 816delGT, 3203del11, and 3347delAG [50, 51]. The first two alterations are founder mutations of BRCA1 gene in Norwegian population and it has been shown that they have less penetrance in them compared to Ashkenazi Jews [52, 53].
In Icelandic BC women, it seems that the rate of BRCA1 mutations is relatively low. The only mutation detected was splice site alteration in exon 17 (Table 2). The only studied BRCA2 mutation, 999del5, is well-known founder mutation of this population which is responsible for 24% of all BC patients who are <40 yrs and was identified in 40% of familial Icelandic BC [54–57].
BRCA1 mutations do not affect risk of bilateral breast tumors in Dutch high risk individuals. Two frame shift deletions (del3835, 2804delAA) and the 1411insT single base insertion mutation have been recognized as founder alterations of Netherland. Furthermore, the 2804delAA deletion occurs in Alu repeat that disrupts the exon 13 and exon 22 sequences [58, 59].
5.3. Central and Southern Europe
All the mutations regarding Central and southern European population were brought in Table 3. In an Estonia population study, the well-known c.4154delA and c.5382insC rearrangements were found in 63.6% and 27% of all alterations, respectively. In addition, two novel frame shift deletions (c.6631delTTAAATG and c.3881-3882delGA) were recognized in exon 11 of BRCA1 gene which cause too early termination of translation. The c.4158A>G, c.4427T>C polymorphisms, similar to the previous studies showed no clinical adverse effects on BRCA1 protein structure and function .
The c.3228_3229delAG and c.3285delA deletions in BRCA1 gene are the most important and prevalent mutations of Italian populations (57%). The latter was found initially in Italian studies but the former mutation had high frequency only in male BC cases which may propose a mechanism for involvement of this deletion type in male BC pathogenesis. Once more, the founder alterations, c.1377_1378insA and c.5062_5064delTGT (72% of all BRCA1 variants), were identified in BRCA1 gene. Truncated BRCA2 protein is created as a result of c.289G>T, c.2950G>T, c.7963C>T, and c.8878C>T mutations generating premature stop codon, and except of the last one, all of them were primarily detected in Italy. Screening for LGRs is important in Italian high risk families as they compose 19% of all the alterations usually affecting the BRCA1 gene [61, 62]. Two new premature stop codon insertion/deletion mutations (7525_7526insT and 6174delT) were detected in exon 15 of BRCA2 in Italian BC women. They occur in C-terminal of protein and are associated with disruption of nuclear localization signals (NLSs) which interfere with BRCA2 nuclear penetration and participation in DNA repair process . The significance of these alterations is due to their important role in drug resistance especially PARP inhibitors . The BRCA1 and BRCA2 mutations screening program in Italian population was extended in BC patients from Apulia where two major missense polymorphisms, including S1613G (exon 16) and K1183R (exon11), were identified in BRCA1 gene contributing to BC risk .
Spanish studies could discover two major founder mutations with low frequency in both BRCA1/2 genes, the 330A>G substitution change in splice site between exon 5 and exon 6 which makes an inefficient truncated form of BRCA1 protein . The second change, 9254del5 in BRCA2 gene, was also detected in French families . However, the recent Spanish study introduced exons 3–5 del (g.8097_22733del14637) within the BRCA1 gene as as a new primarily identified Spanish founder mutation among Valencian women . The most frequent insertion/deletion mutations which occur in this population include c.187_188delAG and c.5385insC in BRCA1 gene and c.9254_9258delATCAT along with c.3492_3493insT in BRCA2 gene. Furthermore, investigations among 1,763 hereditary BC and ovarian cancer (OC) families have recently found that c.66_68delAG, c.5123C>A, c.1961delA, c.3770_3771delAG, and c.5152+5G>A mutations were in 45.2 % of BRCA1 mutation carriers. In addition, c.9026_9030delATCAT, c.3264insT, and c.8978_8991del14 comprised the 43.2% of BRCA2 alterations . It was revealed that the deletion of 6 flanking exons (8–13) which also was detected in French BC patients is as a result of Alu repeat recombination in juxtaposed introns. Among all the SNPs found for BRCA1 and BRCA2 genes in Spanish persons, it seems that only 9475A>G could affect structure and function of BRCA2 protein. Another Spanish population in North America (Colorado) demonstrated the same pattern in the absence of 5382insC and 6174delT and the presence of 185AGdel Ashkenazi Jews founder mutations, that is, similar to other Spanish studies . The presence of Spanish family who suffered from ovarian cancer and early onset ovarian cancer or BC is a major clue for the screening of BRCA1 and BRCA2 gene mutations .
The general prevalence of rearrangement in BRCA1 gene was 3% in German BC patients and their families. Such low prevalence was also already reported in Finnish and Danish BC patients . However, the most common mutations of the Germany patients comprise 55% of all the mutations of BRCA1 and BRCA2 genes including loss of exon 22 and exon 17 as founder deletions in BRCA1 besides deletion of exon 13. Alu repeat slipped misspairing in this gene is responsible for these duplication/deletion aberrations. BRCA2 gene mutations were found to be very rare in German BC families [70, 71]. Role of Alu repeat rearrangements of BRCA1 and BRCA2 genes in BC pathogenesis has turned out to be more prominent in Portuguese population studies. The most prevalent mutation (1/4 of all BRCA1 and BRCA2 mutations) and founder insertion are c.156-157ins Alu. It is a targeted insertion rather than random integration of 350 bps from Alu Ya5 subfamily into the exon 3 of BRCA2 gene leading to its deletion and consequent loss of transactivation domain. It has been shown that this insertion type is responsible for about 36% of BRCA gene mutations in male BC families and definite identification of this insertion increases the overall detection rate of BRCA1 and BRCA2 alterations up to approximately 13% . Another type of insertion occurs in BRCA1 gene through rearrangement in Alu Sp/Sq repeat family .
French population has shown its own specific founder BRCA mutations too. BRCA1 and BRCA2 2 mutations account for more than 40% of all French families affected by BC, particularly, in younger ages . All of the most important mutations of this population are represented in Table 3. It was suggested that the alterations of nucleotides in spectrum of 2401–4191 in BRCA1 gene are associated with either low risk BC or high risk ovarian cancer. Moreover, rare cases of LGRs were detected among BC patients with origin of French but not in French-Canadian . Although two of the frequent mutations (6503delTT and 3398delAAAAG) take place in ovarian cancer critical region (OCCR) located in exon 11 of BRCA2, there is no difference in risk of ovarian cancer among the carriers of theses mutations and others which are carriers of mutations in other part of BRCA2 gene . A large deletion encompassing exons 8–13 of BRCA1 gene and the duplication of exons 3–8 and exon 18–20 were identified in French BC families . The French-Canadian BC families share a common mutation (8765delAG) in BRCA1 gene with Jews of Yemenites origins . It is interesting that except of one founder deletion in BRCA1 gene (c.1592delT), the researchers could not find any duplication or deletion mutations in BRCA1 and BRCA2 genes in French origin inhabiting in Canada compared to those in France. Among all of the variants that were detected in both BRCA1 and BRCA2 genes, only the c.5095>T has considerable clinical impact on BRCA1 function .
The BRCA1 and BRCA2 mutation studies have been performed in the Anglia, British, Scottish, Welsh, and Irish populations (Table 3). The Scottish and Irish BC patients were carriers of two Ashkenazi Jews founder mutations, 185 delAG and 5382 insC which include the most frequent BRCA1 and BRCA2 mutations, respectively. Interestingly, the 4184 del4 mutation in BRCA1 has been found in BC patients with Welsh, South Thames, Oxford, Yorkshire, Irish, and Scottish origin [78–80].
5.4. Eastern Europe
All the mutations regarding Eastern European population were brought in Table 4.
Alu insertion in intronic sequences was detected in Czech population in intron 3 of BRCA1 gene made by AluSx (g.17686–17695) and AluY (g.18760–18769) repeats rearrangements and in intron 10 by means of AluJb (g.33248–33276) sequence recombination. In addition, deletion of exons 21–24 in BRCA1 gene also was demonstrated in this population which is as a result of Alu repeats recombination. It is important in BRCA genes mutations screening to note that the deletion of exons 5–14 (the most prevalent rearrangement in Czech) and all of the first 17 exons of BRCA1 gene is specific to the Czech BC patients and is also considered as founder mutations .
The Slovenian BC cases demonstrated the three main mutations in BRCA1: c.1687C>T, 5382insC, c.844_850dupTCATTAC, and c.181T>G, with rate of 56, 32, 37.3, and 30% of all BC cases respectively. Replication of the first three mentioned mutations of BRCA1 gene in different Slovenian sample studies is relying on their consideration in mutation screening of this population [82–84]. Among the mutations detected in BRCA2 gene, the most and the least frequent changes (c.7806-2A>G and c.3975_3978dupTGCT) were recognized in male BC cases. Additionally, c.7806-2A>G and c.5291C>G are only defined in Slovenian populations, and c.7806-2A>G and IVS16-2A> were considered as a founder mutation of this region [83, 85]. In an assay on 379 HBOC Slovenian families, c.181T>G, c.1687C>T, and c.844_850dupTCATTAC were the most frequent BRCA1 mutations while c.7806-2A>G splicing alteration which was found in 13 families was the most BRCA2 one .
In polish populace, in addition to the most frequent variants including 5382insC (exon 20), Cys61Gly (exon 5), and 185delAG (exon 2), two new insertion/deletion mutations were identified in BRCA1 and BRCA2 recently (2991del5 and 6238ins2del21, resp.). 5382insC and 300T>G (Cys61Gly) were supposed as founder mutations in various polish studies [87, 88]. A new c.190T>G mutation of this population in BRCA1 gene is associated with activation of a cryptic splice site in exon 5 and leads to truncated protein by deletion of 22 nucleotides . In general, there is a high trend in BRCA1 mutation screening among this population due to their high frequency even in BC patients without familial history .
In Greek territory, two major mutations were described. After 5382insC, G1738R is the most important and frequent mutation which occurs in exon 20 of BRCA1 gene. The pathogenic effect of G1738R alteration was confirmed in many studies. It seems that G to A base pair exchange is associated with disruption of protein folding influencing the interaction of BRCA1 with DNA damage-associated kinas BACH1 [25, 91, 92].
The incidence of BRCA1 and BRCA2 gene alterations in middle and south regions are about twice that in north of Sardinia (17-18% against 7% in north). The c.1632 A>T, c.1638 A>T missense mutations and two deletions (c.3823_3826delACAA and c.4575delA) in BRCA1, and the c.3950_3952delTAGinsAT and c.6586 C>G in BRCA2 gene were discovered for the first time in this population and were incorporated in BC information center (BIC). The c.8764_8765delAG and c.3950_3952delTAGinsAT del/ins mutations were considered as founder mutations in BRCA2 gene of Sardinian population .
All the mutations regarding American population were represented in Table 5. However, there are some unpublished mutations acquired by next generation sequencing in Myriad Genetic Laboratories (Salt Lake City, UT) provided by BIC. In America, BRCA1/2 mutation screening has been extended to genetic analysis of biological samples and sending reports via online genetic testing in centers as well as Myriad Genetic Laboratories which has arisen some debates regarding ethics of information obtained. However, there are several reports of various BRCA1 and BRCA2 mutations found in different states of America.
In the BC families who were genotyped from Boston, 6697delTC has been shown as the most frequent mutation accompanying the three major Ashkenazi Jews insertion/deletions. Nevertheless, the same study in Washington could not find the 185AGdel .
In another USA study which was carried out on more than 300 BC families, the AluSx/Sx (dup 9700) and AluSx/Sp (del2352ins12) rearrangements were demonstrated in BRCA2 genes of patients with English and Dutch in addition to German origin, respectively. Some other BRCA1 gene rearrangements including AluY, AluJ, AluJO, AluSg, AluSp, AluSx, AluSq, and AluSc were identified in cases with other European ancestry. All of these Alu rearrangements took place in exons unlike those occurring in introns in Nigerian BC patients screened in USA . Another large 36.4 kb deletion as a result of Alu rearrangement (exons 9–19 del) was found in a Brazilian BC patient affected by Li-Fraumeni syndrome . Moreover, a smaller deletion, exons 9–12 del, was identified in a Hispanic survey which is considered as Mexican founder BRCA1 alteration with high frequency (10–12%) . C61G which was formerly reported in Latvia and Belarus studies was identified in a USA survey among Caucasian women with triple negative breast cancer . In another USA assay which investigated a diverse population of African American, Asian, Hispanic or none-Hispanic Ashkenazi Jews, and non-Jewish whites, the 185AGdel in different haplotype of Ashkenazi Jews was found in a woman with Irish/German origin which was never detected neither in German or Irish population . In three German families, 5950delCT was identified in BRCA2 gene as expected from previously performed German population studies .
Pattern of BRCA1 and BRCA2 mutation was different in Southern USA studies (Table 5). The 185AGdel and 5382ins mutations have been found in Chile and Brazil assays, respectively. Study in Bahamas which is located in Central USA (a Caribbean island) showed that this population harbors the most frequency of BRCA1 mutations (22.9%) [39, 101–104]. It was approved in a recent study on 214 Bahamian women affected by breast cancer with or without family history. 27% of them were carriers of either BRCA1 or BRCA2 mutations more than any other population .
BC incidence is the most in Pakistan compared to other Asian populations. However, BRCA1 and BRCA2 mutations play pivotal role in only 12% of all BC cases. Four truncation and frame shift in addition to one splice site mutations in BRCA1 gene (3889delAG, 2080insA, 4284delGA, 4184del4, and IVS14-1ArG) and the missense 3337C>T mutation in BRCA2 gene comprise the directory of founder mutations of this population. The truncated protein producing by c.4627C>A substitution is the most common alteration in BRCA1 gene. Punjab embraces the ethnicity harboring the most rate of BRCA1 mutations (57%) with great difference versus Muhajir groups (17%). The same situation is held for BRCA2 mutations (33%) against multiracial women (28%) . The 4627C>A, 185delAG, and 185insA mutations of BRCA1 which are accumulated in northern and eastern Pakistan are considered as founder alterations as 185delAG is for Pathaan, and 185insA accompanying 4627C>A is specific to Punjabi women .
Regardless of deletion in other populations, the LGRs which are associated with amplification were initially detected in exons 3 and 10 of BRCA1 gene in two Malaysian women who both were affected with sporadic BC . However, a multiethnic study on BC Malaysian demonstrated that the frequency of TP53 mutations is superior to BRCA1/2 genes alterations especially in patients with positive family history which could make BRCA1/2 mutation screening debatable .
The c.7480C>T mutation includes 25%–50% (in different samples) of all mutations happening in BRCA2 and is assumed as founder and the most common alteration of BRCA1 and BRCA2 genes in Korean BC women especially those who are positive for familial history and have bilateral or multifocal tumors. Among all mutations which were found in both familial and sporadic BC cases [110, 111], exon 11 was more influenced by several insertions/deletions and single base pair frame shift mutation in both BRCA1 and BRCA2 gene. It is noticeable that only one LGR (c.4186-1593_4676-1465del) and in only BRCA1 gene was reported in this population . The 1627A.T (exon 10), 3972delTGAG (exon 11), and 7708C.T (exon 15) harmful mutations in BRCA2 were replicated in multiple Korean population studies .
It is obvious that in Japanese BC patients like Korean and Cypriot ones , the role of BRCA2 mutations is more frequent and important than BRCA1. However, among three founder Japanese alterations, the truncation mutation in codon 63 and an insertion in exon 22 are located in BRCA1 and the third one was found in BRCA2 gene (5802del AATT). In addition the pattern of accumulation of mutations in exon 11 of either BRCA1 or BRCA2 genes mimics the Korean population [114, 115].
Several Chinese studies have relied on the three major mutations in BRCA1 gene including 3478del5, 5589del8, and 1100delAT, with the first being only annotated in Chinese women [116, 117]. It was suggested that both of them are considered as founders of north China. These mutations have shown correlation only with familial not sporadic BC [118, 119]. Another founder mutation of BRCA1 has been introduced which is specific to BC patients from Hong Kong and southern China (Table 6) [120, 121].
It is surprising that the 185delAG deletion takes place in high incidence of 16.3% in Indian population near the frequency of 18% in Ashkenazi Jews. In addition, the role of BRCA2 mutations is meaningless in Indian BC genetics especially in earlier ages [122–125]. In this way, more focus on BRCA1 gene mutations led to uncovering two 1014delGT and 3889delAG premature stop codon deletions in addition to 5382insC in BC patients from North-East and Eastern India, respectively [126, 127].
In a recent mutation screening of BRCA1 gene on Russian 7920 normal and 570 BC patients, each of 185delAG and 4153delA mutations were identified in only one BC case. However, 5382insC and 300 T>G were recognized in both normal and BC groups . 5382insC and 4153delA had been identified in three previous Russian studies while 5382insC had shown more frequency than 1100delC mutation of CHEK2 among Siberian BC patients compared to healthy controls [129–131].
Based on piecewise Weibull model and in a kin-cohort analysis, we have found that the BRCA1/2 mutations penetrance seems to be lower among Iranian breast cancer families as it was reported 31.9% and 46.2% for women aged lower and more than 50 years old, respectively . In the Iranian BRCA1 mutation analysis, DNA samples of 80 early onsets BC patients were undergone PCR sequencing. The novel 1534G>A substitution was detected in exon 16 of BRCA1 in 38.6 of BC patients as well as 52.8% of healthy controls. They could find another mutation in exon 15 of BRCA1 besides eight variants in which Pro871Lue and Glu1038Gly were identified in the same haplotypes. Moreover, it was shown that Leu871 was significantly more in controls versus patients () which is inconsistent with previous studies implying the higher frequency amongst BC patients . Yassaee and his coworkers found a polymorphism (duplication of 12 base pairs in IVS20+48) in exon 20 of BRCA1 gene along with 6261insGT inside the BRCA2 gene in a 27-years-old BC patient. One patient showed IVS16-14T>C within exon 17 of BRCA2 close to the splice site which has been previously reported in British population. They have reported the 5382insC in 19% of their familial BC patients, with possible role of it as a founder mutation of Iranian nonfamilial BC cases . The novel G2031T base pair exchange was determined in BRCA1 gene through investigation of exons 2, 20, and 11 in an Iranian family who suffered from hereditary breast cancer and ovarian cancer syndrome . We performed mutation screening of all coding and 3′ and 5′ UTR sequences of BRCA1 and BRCA2 genes on ten high risk breast cancer families. A novel BRCA2 mutation c.4415 4418delAGAA was discovered and insertion c.6033_6034insGT was also found which could lead to premature termination of translation at the codons 1477 and 2040, respectively. In BRCA1 gene, the IVS17-53C>T and g.381-389del9ins29 of 3′ UTR were found. The latter was detected in two families, in one of those two affected sisters and their healthy mother were negative for g.381-389del9ins29 of 3′ UTR alteration ; such familial screening has a positive clinical impact on the quality of life of proband’s relatives and could be considered as a personalized management. By considering the specific screening program in our study, the 185delAG was found in one BC patient and her sister was affected with meningioma in age of 46 and 35 yrs, respectively, and also in another proband from separate family. We could identify neither 5382insC nor 6174delT in the studied population . The same study was conducted by Fattahi and his colleagues in which no Ashkenazi Jews alteration was found . However, the 5382insC in 20% of their familial BC patients was reported . Some other novel mutations were detected in BRCA1 (p.Glu1735 p.Gly1140Ser, p.Ile26Val, p.Leu1418X, p.Glu23Gln, p.Leu3X, p.Asn1403His, p.Lys581X, p.Pro938Arg, p.Thr77Arg, p.Arg7Cys, p.Ser177Thr, IVS7+83(TT), IVS8-70(-CATT), IVS2+9(-GC), IVS1-20(-GA), IVS1-8(-AG), IVS2+24(AG), IVS5-8 (A-G), and IVS2(35–39)TTCCTATGAT) and in BRCA2 (p.Glu1391Gly, 1994_1995 (Ins A), and IVS6-70-T>G) genes recently .
An Iranian BC patient who was also none-Ashkenazi Jewish has demonstrated a founder mutation in BRCA1 gene (Tyr978X) as well as Iraqi, Afghani, and Canadian BC patients from Israel . It was replicated in a later study carried out in Israel among non-Ashkenazi Asian BC patients . This mutation was not previously detected in the same non-Jewish Iranian and Iraqi populations .
All the mutations regarding the USA African population have been compiled in Table 8.
In all the few African population assays which we have reviewed, only Egyptian women demonstrated founder mutations in both BRCA1 and BRCA2 genes. However, African triple negative BC patients from USA showed 943ins10 mutation of BRCA1 as founder of West Africa . The deletion of exon 21 in BRCA1 gene was identified in a woman who was one of the 352 participants Nigerian BRCA screening. This deletion is a result of unequal crossing-over of AluSg and AluY repeat from introns 20 and 21, respectively . Two major Ashkenazi Jews mutations of BRCA1 gene, 185AGdel and 5382insC, were identified in Egyptian and Tunisian women, respectively. The c.798_799delTT alteration of BRCA1 was shown in Tunisian BC cases from Algeria . However, the 185AGdel founder alteration was found in two independent screening tests of Jewish and non-Jewish Morocco population . The 5999del4 mutation was found to be a founder BRCA2 mutation of Western Cape Province which had been found previously in Dutch population without any evidence of common ancestry for these two populations . Moreover, in a recent study, c.798_799delTT was introduced as a non-Jewish founder BRCA1 gene identified in Tunisian and Algerian BC patients and their families inhabitant in Northwest Africa (Morocco) .
5.8. Other Continents and Islands
Another population that is famous to have founder mutation is Greenland. In addition to 234T>G and 249T>A founder mutations which were originated from Danish population, the 4803delCC, p.Cys44Phe p.Cys44Tyr (c.131G>A), and p.Cys44Ala should be considered in mutation screening of BRCA1 in Greenlandic women .
Although in Australia continent the role of insertion/deletion mutations in BRCA1 and BRCA2 genes is weaker, some single nucleotide polymorphisms (SNP) showed significant association with BC risk which was discussed in polymorphism section. No important, founder and frequent BRCA1 and BRCA2 mutation was yet reported in Australian studies .
6. Clinical-Pathological Correlation with BRCA1 and BRCA2 Mutations
The effect of BRCA1 and BRCA2 mutations on histological and pathological state, stage, and grade of BC, especially the involvement of lymph nodes, is determining factor of BCs prognosis and survival rate. In general, the carriers of BRCA1 and BRCA2 show higher tumor stage, grade and ER negative tumors, and more metastasis to neighbor vessels relative to those who harbor other gene mutations . It was in agreement with approximately all of ethnics and population especially Asian BC families compared to non-BRCA1 and -BRCA2 mutations, and also among the BRCA1 and BRCA2 alterations, BRCA1 mutations are associated with higher tumor grade, P53 mutations and higher basal cell markers including cytokeratin [150, 151] and P-cadherin expression while underexpression of E-cadherin in triple negative BC cases of younger ages (estrogen, progesterone, and Her2 receptors) and eventually weaker prognosis [116, 152]. In addition, we have reported that significant correlation was found between expression of BRCA1 gene and degree of tumor as upregulated gene expression was related to the higher tumor grade .
Therefore, it seems that hormones disturbances have no role in the development of BC in BRCA1 and BRCA2 mutations carriers. Moreover, BRCA1 mutations frequently occur in medullary especially atypical BC with higher mitotic index (>50/10HPF) versus tubular and intraductal ones which are more seen in BRCA2 mutations. Another tumor morphology pattern of BRCA1 carriers comprise of pushing margins which avoid of tubular formation, trabecular, syncytial and circumscribed growth pattern and necrosis . However, a recent study on American population has demonstrated higher significant survival (relapse-free survival or RFS) in both BRCA1 and BRCA2 carriers compared to non-BRCA BC cases . It was shown that some LGRs in BRCA1 gene including exons 17 and 20 deletions were associated with previously defined tumor morphology .
It is noticeable that the French BRCA1 and BRCA2 mutation carriers are usually negative for lymph nodes involvement and contralateral form of BC. However they have shown higher tumor stage and lower rate of ductal in situ carcinoma .
The most frequent BRCA1 gene mutation is 5382insC (c.5266dupC) which was found in roughly all of the populations. The maximum likelihood method considering any mutation or crossing-over occurrence has shown that this insertion at first came from Scandinavia probably Denmark as it comprises the founder mutation in Danish population around 200 AC. However, Russia is another candidate for occupying the primary origin of it and after that it was disseminated to other areas including Ashkenazi Jews. It was also proposed that 5382insC has entered into the Ashkenazi Jewish through affecting Polish population about 400 yrs earlier. 5382insC is the most important and prevalent BRCA1 mutation in European countries even though; Asian and American BC individuals rarely demonstrate it . The second globally frequent BRCA1 mutation is 185AGdel in exon 2 and was described in all the ethnics including Asia, America, Africa, and European populations. Since, it was replicated in various populations with Arabic ethnics including Syria, Iraq, and Yemen, considering this deletion in screening high risk families with Arab ethnics may be helpful. The third most frequent BRCA1 alteration is 300T>G which has mainly determined in East European populations in addition to Germany. It is interesting that African American population from USA have demonstrated 300T>G as a recurrent BRCA1 mutation . Shedding light on the common ancestry of this mutation in two unrelated African American and Eastern European populations may be helpful for finding a logical way to consider it in screening programs of other related populations. Except of the most recurrent mutations which were described, approximately all of the populations, even among the same ethnics, show different BRCA1 and BRCA2 mutation may patterns. Although with inventing the new mutation screening methods like next generation sequencing knowing the most frequent BRCA1 and BRCA2 mutations not be required, some countries especially the developing countries may take some advantages. In addition, if we have the most recurrent BRCA1 and BRCA2 mutations of our ethnics or population, the diagnosis and treatment of BC patients and the process of followup of their family get faster and better.
Taken together, paying attention to the frequent mutations facilitates analysis in high risk members of BC families in all populations worldwide.
|ATM:||Ataxia telangiectasia mutated|
|BASC:||BRCA1-associated genome surveillance complex|
|BIC:||BC information center|
|BRCT:||BRCA1 C Terminus|
|DBD:||Double strand break domain|
|DNA:||Deoxy nucleic acid|
|LGRs:||Large genomic rearrangements|
|OCCR:||Ovarian cancer cluster region|
|NLS:||Nuclear localization signal|
|SNP:||Single nucleotide polymorphisms.|
Conflict of Interests
The authors report no conflict of interests.
The authors would like to acknowledge Mrs. A. Amirloo for her valuable advises and information on geographic distribution and the origin of population ancestry.
- D. M. Parkin, F. Bray, J. Ferlay, and P. Pisani, “Global cancer statistics, 2002,” Ca Cancer Journal for Clinicians, vol. 55, no. 2, pp. 74–108, 2005.
- A. Sadjadi, M. Nouraie, A. Ghorbani, M. Alimohammadian, and R. Malekzadeh, “Epidemiology of breast cancer in the Islamic Republic of Iran: first results from a population-based cancer registry,” Eastern Mediterranean Health Journal, vol. 15, no. 6, pp. 1426–1431, 2009.
- K. M. Kuusisto, A. Bebel, M. Vihinen, J. Schleutker, and S.-L. Sallinen, “Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals,” Breast Cancer Research, vol. 13, no. 1, article R20, 2011.
- J. M. García, J. Silva, C. Peña et al., “Promoter methylation of the PTEN gene is a common molecular change in breast cancer,” Genes Chromosomes and Cancer, vol. 41, no. 2, pp. 117–124, 2004.
- J. Chen and A. Lindblom, “Germline mutation screening of the STK11/LKB1 gene in familial breast cancer with LOH on 19p,” Clinical Genetics, vol. 57, no. 5, pp. 394–397, 2000.
- P. A. Steck, M. A. Pershouse, S. A. Jasser et al., “Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers,” Nature Genetics, vol. 15, no. 4, pp. 356–362, 1997.
- K. A. Schrader, S. Masciari, N. Boyd et al., “Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers,” Journal of Medical Genetics, vol. 48, no. 1, pp. 64–68, 2011.
- P. Mehdipour, M. Mahdavi, J. Mohammadi-Asl, and M. Atri, “Importance of ATM gene as a susceptible trait: predisposition role of D1853N polymorphism in breast cancer,” Medical Oncology, vol. 28, no. 3, pp. 733–737, 2011.
- P. Mehdipour, L. Habibi, J. Mohammadi-Asl, N. Kamalian, and M. Mehr Azin, “Three-hit hypothesis in astrocytoma: tracing the polymorphism D1853N in ATM gene through a pedigree of the proband affected with primary brain tumor,” Journal of Cancer Research and Clinical Oncology, vol. 134, no. 11, pp. 1173–1180, 2008.
- A. Celebiler Cavusoglu, Y. Kilic, S. Saydam et al., “Predicting invasive phenotype with CDH1, CDH13, CD44, and TIMP3 gene expression in primary breast cancer,” Cancer Science, vol. 100, no. 12, pp. 2341–2345, 2009.
- E. M. Rosen, S. Fan, R. G. Pestell, and I. D. Goldberg, “BRCA1 in hormone-responsive cancers,” Trends in Endocrinology and Metabolism, vol. 14, no. 8, pp. 378–385, 2003.
- L. Moore-Smith and B. Pasche, “TGFBR1 signaling and breast cancer,” Journal of Mammary Gland Biology and Neoplasia, vol. 16, no. 2, pp. 89–95, 2011.
- D. F. Easton, “How many more breast cancer predisposition genes are there?” Breast Cancer Research, vol. 1, no. 1, pp. 14–17, 1999.
- J. Zhang, J. D. Fackenthal, D. Huo, Y. Zheng, and O. I. Olopade, “Searching for large genomic rearrangements of the BRCA1 gene in a Nigerian population,” Breast Cancer Research and Treatment, vol. 124, no. 2, pp. 573–577, 2010.
- P. J. O'Donovan and D. M. Livingston, “BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair,” Carcinogenesis, vol. 31, no. 6, pp. 961–967, 2010.
- T. M. Smith, M. K. Lee, C. I. Szabo et al., “Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1,” Genome Research, vol. 6, no. 11, pp. 1029–1049, 1996.
- C. G. Murphy and M. E. Moynahan, “BRCA gene structure and function in tumor suppression: a repair-centric perspective,” Cancer Journal, vol. 16, no. 1, pp. 39–47, 2010.
- A. R. Venkitaraman, “Cancer susceptibility and the functions of BRCA1 and BRCA2,” Cell, vol. 108, no. 2, pp. 171–182, 2002.
- D. Thompson and D. Easton, “The genetic epidemiology of breast cancer genes,” Journal of Mammary Gland Biology and Neoplasia, vol. 9, no. 3, pp. 221–236, 2004.
- M. Pisanò, V. Mezzolla, M. M. Galante et al., “A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history,” Familial Cancer, vol. 10, no. 1, pp. 65–71, 2011.
- S. Tommasi, A. Crapolicchio, R. Lacalamita et al., “BRCA1 mutations and polymorphisms in a hospital-based consecutive series of breast cancer patients from Apulia, Italy,” Mutation Research, vol. 578, no. 1-2, pp. 395–405, 2005.
- E. Manguoĝlu, Ş. Güran, D. Yamaç et al., “Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients,” Cancer Genetics and Cytogenetics, vol. 203, no. 2, pp. 230–237, 2010.
- W. De Silva, E. H. Karunanayake, K. H. Tennekoon et al., “Novel sequence variants and a high frequency of recurrent polymorphisms in BRCA1 gene in Sri Lankan breast cancer patients and at risk individuals,” BMC Cancer, vol. 8, article 214, 2008.
- G. T. Toh, P. Kang, S. S. W. Lee et al., “BRCA1 and BRCA2 germline mutations in Malaysian women with early-onset breast cancer without a family history,” PLoS ONE, vol. 3, no. 4, Article ID e2024, 2008.
- I. Konstantopoulou, C. Kroupis, A. Ladopoulou et al., “BRCA1 mutation analysis in breast/ovarian cancer families from Greece,” Human Mutation, vol. 16, no. 3, pp. 272–273, 2000.
- A.-Y. Cao, J. Huang, Z. Hu et al., “Mutation analysis of BRIP1/BACH1 in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives,” Breast Cancer Research and Treatment, vol. 115, no. 1, pp. 51–55, 2009.
- M. Loizidou, B. Marcou, V. Anastasiadou, R. Newbold, A. Hadjisavvas, and K. Kyriacou, “Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early-onset breast cancer in Cyprus,” Clinical Genetics, vol. 71, no. 2, pp. 165–170, 2007.
- E. Machackova, L. Foretova, M. Lukesova et al., “Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer,” BMC Cancer, vol. 8, article 140, 2008.
- T. Distelman-Menachem, T. Shapira, Y. Laitman et al., “Analysis of BRCA1/BRCA2 genes' contribution to breast cancer susceptibility in high risk Jewish Ashkenazi women,” Familial Cancer, vol. 8, no. 2, pp. 127–133, 2009.
- A. B. Spurdle, S. R. Lakhani, S. Healey et al., “Clinical classification of BRCA1 and BRCA2 DNA sequence variants: the value of cytokeratin profiles and evolutionary analysis—a report from the kConFab investigators,” Journal of Clinical Oncology, vol. 26, no. 10, pp. 1657–1663, 2008.
- C. Augello, L. Bruno, V. Bazan et al., “Y179C, F486L and N550H are BRCA1 variants that may be associated with breast cancer in a Sicilian family: results of a 5-year GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study,” Annals of Oncology, vol. 17, no. 7, supplement, pp. 30–33, 2006.
- L. Wei, L. Lan, Z. Hong, A. Yasui, C. Ishioka, and N. Chiba, “Rapid recruitment of BRCA1 to DNA double-strand breaks is dependent on its association with Ku80,” Molecular and Cellular Biology, vol. 28, no. 24, pp. 7380–7393, 2008.
- D. Torres, M. U. Rashid, F. Gil et al., “High proportion of BRCA1/2 founder mutations in Hispanic breast/ovarian cancer families from Colombia,” Breast Cancer Research and Treatment, vol. 103, no. 2, pp. 225–232, 2007.
- A. Pietschmann, P. Mehdipour, M. Atri et al., “Mutation analysis of BRCA1 and BRCA2 genes in Iranian high risk breast cancer families,” Journal of Cancer Research and Clinical Oncology, vol. 131, no. 8, pp. 552–558, 2005.
- A. Hadjisavvas, E. Charalambous, A. Adamou, C. G. Christodoulou, and K. Kyriacou, “BRCA2 germline mutations in Cypriot patients with familial breast/ovarian cancer,” Human Mutation, vol. 21, no. 2, p. 171, 2003.
- A. Hadjisavvas, E. Charalambous, A. Adamou, S. L. Neuhausen, C. G. Christodoulou, and K. Kyriacou, “Hereditary breast and ovarian cancer in Cyprus: identification of a founder BRCA2 mutation,” Cancer Genetics and Cytogenetics, vol. 151, no. 2, pp. 152–156, 2004.
- L. Turkovic, L. C. Gurrin, M. Bahlo, G. S. Dite, M. C. Southey, and J. L. Hopper, “Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age,” BMC Cancer, vol. 10, article 466, 2010.
- M. Soegaard, S. K. Kjaer, M. Cox et al., “BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark,” Clinical Cancer Research, vol. 14, no. 12, pp. 3761–3767, 2008.
- L. Jara, S. Ampuero, E. Santibáñez et al., “BRCA1 and BRCA2 mutations in a South American population,” Cancer Genetics and Cytogenetics, vol. 166, no. 1, pp. 36–45, 2006.
- M. D. Miramar, M. T. Calvo, A. Rodriguez et al., “Genetic analysis of BRCA1 and BRCA2 in breast/ovarian cancer families from Aragon (Spain): two novel truncating mutations and a large genomic deletion in BRCA1,” Breast Cancer Research and Treatment, vol. 112, no. 2, pp. 353–358, 2008.
- L. Negura, N. Uhrhammer, A. Negura, V. Artenie, E. Carasevici, and Y.-J. Bignon, “Complete BRCA mutation screening in breast and ovarian cancer predisposition families from a North-Eastern Romanian population,” Familial Cancer, vol. 9, no. 4, pp. 519–523, 2010.
- L.-X. Qiu, L. Yao, K. Xue et al., “BRCA2 N372H polymorphism and breast cancer susceptibility: a meta-analysis involving 44,903 subjects,” Breast Cancer Research and Treatment, vol. 123, no. 2, pp. 487–490, 2010.
- Z. K. Stadler, E. Salo-Mullen, S. M. Patil et al., “Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer,” Cancer, vol. 118, no. 2, pp. 493–499, 2012.
- C. V. Dillenburg, I. C. Bandeira, T. V. Tubino et al., “Prevalence of 185delAG and 5382insC mutations in BRCA1, and 6174delT in BRCA2 in women of Ashkenazi Jewish origin in southern Brazil,” Genetics and Molecular Biology, vol. 35, no. 3, pp. 599–602, 2012.
- K. Pylkäs, H. Erkko, J. Nikkilä, S. Sólyom, and R. Winqvist, “Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families,” BMC Cancer, vol. 8, article 146, 2008.
- J. M. Hartikainen, A. Mannermaa, S. Heinonen, V.-M. Kosma, and V. Kataja, “A BRCA2 mutation, 4088insA, in a finnish breast and ovarian cancer family associated with favourable clinical course,” Anticancer Research, vol. 27, no. 6 C, pp. 4295–4300, 2007.
- N. Loman, O. Johannsson, U. Kristoffersson, H. Olsson, and Å. Borg, “Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer,” Journal of the National Cancer Institute, vol. 93, no. 16, pp. 1215–1223, 2001.
- S. Håkansson, O. Johannsson, U. Johansson et al., “Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer,” American Journal of Human Genetics, vol. 60, no. 5, pp. 1068–1078, 1997.
- M. Thomassen, T. V. O. Hansen, Å. Borg et al., “BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer,” Acta Oncologica, vol. 47, no. 4, pp. 772–777, 2008.
- T. L. Bodd, J. Reichelt, K. Heimdal, and P. Møller, “Uptake of BRCA1 genetic testing in adult sisters and daughters of known mutation carriers in Norway,” Journal of Genetic Counseling, vol. 12, no. 5, pp. 405–417, 2003.
- P. Møller, K. Heimdal, J. Apold et al., “Genetic epidemiology of BRCA1 mutations in Norway,” European Journal of Cancer, vol. 37, no. 18, pp. 2428–2434, 2001.
- A. Dørum, K. Heimdal, E. Hovig, M. Inganäs, and P. Møller, “Penetrances of BRCA1 1675delA and 1135insA with respect to breast cancer and ovarian cancer,” American Journal of Human Genetics, vol. 65, no. 3, pp. 671–679, 1999.
- K. Heimdal, L. Mæhle, J. Apold, J. C. Pedersen, and P. Møller, “The Norwegian founder mutations in BRCA1: high penetrance confirmed in an incident cancer series and differences observed in the risk of ovarian cancer,” European Journal of Cancer, vol. 39, no. 15, pp. 2205–2213, 2003.
- H. Gunnarsson, A. Arason, E. M. Gillanders et al., “Evidence against PALB2 involvement in Icelandic breast cancer susceptibility,” Journal of Negative Results in BioMedicine, vol. 7, no. 1, article 5, 2008.
- H. Tulinius, J. E. Eyfjord, G. H. Olafsdottir et al., “The effect of a single BRCA2 mutation on cancer in Iceland,” Journal of Medical Genetics, vol. 39, no. 7, pp. 457–462, 2002.
- S. Thorlacius, G. Olafsdottir, L. Tryggvadottir et al., “A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes,” Nature Genetics, vol. 13, no. 1, pp. 117–119, 1996.
- L. Tryggvadottir, H. Sigvaldason, G. H. Olafsdottir et al., “Population-based study of changing breast cancer risk in Icelandic BRCA2 mutation carriers, 1920–2000,” Journal of the National Cancer Institute, vol. 98, no. 2, pp. 116–122, 2006.
- H. Papelard, G. H. De Bock, R. Van Eijk et al., “Prevalence of BRCA1 in a hospital-based population of Dutch breast cancer patients,” British Journal of Cancer, vol. 83, no. 6, pp. 719–724, 2000.
- A. H. Van Der Hout, A. M. W. Van Den Ouweland, R. B. Van Der Luijt et al., “A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting,” Human Mutation, vol. 27, no. 7, pp. 654–666, 2006.
- K. Tamboom, K. Kaasik, J. Aršavskaja et al., “BRCA1 mutations in women with familial or early-onset breast cancer and BRCA2 mutations in familial cancer in Estonia,” Hereditary Cancer in Clinical Practice, vol. 8, no. 1, article 4, 2010.
- L. Papi, A. L. Putignano, C. Congregati et al., “Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy,” Breast Cancer Research and Treatment, vol. 117, no. 3, pp. 497–504, 2009.
- S. Agata, A. Viel, L. Della Puppa et al., “Prevalence of BRCA1 genomic rearrangements in a large cohort of Italian breast and breast/ovarian cancer families without detectable BRCA1 and BRCA2 point mutations,” Genes Chromosomes and Cancer, vol. 45, no. 9, pp. 791–797, 2006.
- M. Montagna, M. D. Palma, C. Menin et al., “Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families,” Human Molecular Genetics, vol. 12, no. 9, pp. 1055–1061, 2003.
- A. Vega, B. Campos, B. Bressac-De-Paillerets et al., “The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript,” Human Mutation, vol. 17, no. 6, pp. 520–521, 2001.
- B. Campos, O. Díez, F. Odefrey et al., “Haplotype analysis of the BRCA2 9254delATCAT recurrent mutation in breast/ovarian cancer families from Spain,” Human Mutation, vol. 21, no. 4, p. 452, 2003.
- S. Palanca, I. de Juan, G. Perez-Simo et al., “The deletion of exons 3-5 of BRCA1 is the first founder rearrangement identified in breast and/or ovarian cancer Spanish families,” Familial Cancer, vol. 12, no. 1, pp. 119–123, 2013.
- I. de Juan Jiménez, Z. Garci'a Casado, S. Palanca Suela, et al., “Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence,” Familial Cancer, 2013.
- L. G. Mullineaux, T. M. Castellano, J. Shaw et al., “Identification of germline 185delAG BRCA1 mutations in non-Jewish Americans of Spanish ancestry from the San Luis Valley, Colorado,” Cancer, vol. 98, no. 3, pp. 597–602, 2003.
- M. D. Sluiter and E. J. Van Rensburg, “Large genomic rearrangements of the BRCA1 and BRCA2 genes: review of the literature and report of a novel BRCA1 mutation,” Breast Cancer Research and Treatment, vol. 125, no. 2, pp. 325–349, 2011.
- C. Hartmann, A. L. John, R. Klaes et al., “Large BRCA1 gene deletions are found in 3% of German high-risk breast cancer families,” Human Mutation, vol. 24, no. 6, p. 534, 2004.
- S. Engert, B. Wappenschmidt, B. Betz et al., “MLPA screening in the BRCA1 gene from 1,506 German hereditary breast cancer cases: novel deletions, frequent involvement of exon 17, and occurrence in single early-onset cases,” Human Mutation, vol. 29, no. 7, pp. 948–958, 2008.
- P. M. Machado, R. D. Brandão, B. M. Cavaco et al., “Screening for a BRCA2 rearrangement in high-risk breast/ovarian cancer families: evidence for a founder effect and analysis of the associated phenotypes,” Journal of Clinical Oncology, vol. 25, no. 15, pp. 2027–2034, 2007.
- E. Teugels, S. De Brakeleer, G. Goelen, W. Lissens, E. Sermijn, and J. De Grève, “De novo Alu element insertions targeted to a sequence common to the BRCA1 and BRCA2 genes,” Human Mutation, vol. 26, no. 3, p. 284, 2005.
- S. Gad, V. Caux-Moncoutier, S. Pagès-Berhouet et al., “Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families,” Oncogene, vol. 21, no. 44, pp. 6841–6847, 2002.
- E. Rouleau, B. Jesson, A. Briaux et al., “Rare germline large rearrangements in the BRCA1/2 genes and eight candidate genes in 472 patients with breast cancer predisposition,” Breast Cancer Research and Treatment, vol. 133, no. 3, pp. 1179–1190, 2012.
- P. N. Tonin, “The limited spectrum of pathogenic BRCA1 and BRCA2 mutations in the French Canadian breast and breast-ovarian cancer families, a founder population of Quebec, Canada,” Bulletin du Cancer, vol. 93, no. 9, pp. 841–846, 2006.
- A. P. Manning, D. Abelovich, P. Ghadirian et al., “Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families,” Human Heredity, vol. 52, no. 2, pp. 116–120, 2001.
- Scottish/Northern Irish BRCAI/BRCA2 Consortium, “BRCA1 and BRCA2 mutations in Scotland and Northern Ireland,” British Journal of Cancer, vol. 88, no. 8, pp. 1256–1262, 2003.
- J. M. Lancaster, M. E. Carney, J. Gray et al., “BRCA 1 and BRCA2 in breast cancer families from Wales: moderate mutation frequency and two recurrent mutations in BRCA 1,” British Journal of Cancer, vol. 78, no. 11, pp. 1417–1420, 1998.
- J. Peto, N. Collins, R. Barfoot et al., “Prevalence of BRCA1 and BRCA2 gene mutations in patients with early- onset breast cancer,” Journal of the National Cancer Institute, vol. 91, no. 11, pp. 943–949, 1999.
- I. Ticha, Z. Kleibl, J. Stribrna et al., “Screening for genomic rearrangements in BRCA1 and BRCA2 genes in Czech high-risk breast/ovarian cancer patients: high proportion of population specific alterations in BRCA1 gene,” Breast Cancer Research and Treatment, vol. 124, no. 2, pp. 337–347, 2010.
- M. Krajc, V. Zadnik, and S. Novakovic, “Geographical distribution of Slovenian BRCA1/2 families according to family origin: implications for genetic screening,” Clinical Genetics, 2013.
- M. Krajc, E. Teugels, J. Zgajnar et al., “Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families,” BMC Medical Genetics, vol. 9, article 83, 2008.
- V. Stegel, M. Krajc, J. Žgajnar et al., “The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population,” BMC Medical Genetics, vol. 12, article 9, 2011.
- N. Besic, B. Cernivc, J. De Grève et al., “BRCA2 gene mutations in Slovenian male breast cancer patients,” Genetic Testing, vol. 12, no. 2, pp. 203–209, 2008.
- S. Novakovic, M. Milatovic, P. Cerkovnik et al., “Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families,” International Journal of Oncology, vol. 41, no. 5, pp. 1619–1627, 2012.
- M. Ratajska, I. Brozek, E. Senkus-Konefka et al., “BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland,” Oncology Reports, vol. 19, no. 1, pp. 263–268, 2008.
- T. Byrski, “Germline mutation of BRCA1 gene in Polish families with strong aggregation of breast and/or ovarian cancer based on coding sequence analysis using the SSCP method,” Annales Academiae Medicae Stetinensis, vol. 49, pp. 27–43, 2003.
- P. Willems, V. Magri, M. Cretnik et al., “Characterization of the c.190T>C missense mutation in BRCA1 codon 64 (Cys64Arg),” International Journal of Oncology, vol. 34, no. 4, pp. 1005–1015, 2009.
- P. Gaj, A. Kluska, and D. Nowakowska, “High frequency of BRCA1 founder mutations in Polish women with nonfamilial breast cancer,” Familial Cancer, vol. 11, no. 4, pp. 623–628, 2012.
- J. N. M. Glover, “Insights into the molecular basis of human hereditary breast cancer from studies of the BRCA1 BRCT domain,” Familial Cancer, vol. 5, no. 1, pp. 89–93, 2006.
- T. Anagnostopoulos, M. Pertesi, I. Konstantopoulou et al., “G1738R is a BRCA1 founder mutation in Greek breast/ovarian cancer patients: evaluation of its pathogenicity and inferences on its genealogical history,” Breast Cancer Research and Treatment, vol. 110, no. 2, pp. 377–385, 2008.
- G. Palomba, M. Pisano, A. Cossu et al., “Spectrum and prevalence of BRCA1 and BRCA2 germline mutations in Sardinian patients with breast carcinoma through hospital-based screening,” Cancer, vol. 104, no. 6, pp. 1172–1179, 2005.
- A. A. Langston, K. E. Malone, J. D. Thompson, J. R. Daling, and E. A. Ostrander, “BRCA1 mutations in a population-based sample of young women with breast cancer,” New England Journal of Medicine, vol. 334, no. 3, pp. 137–142, 1996.
- T. Walsh, S. Casadei, K. H. Coats et al., “Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer,” Journal of the American Medical Association, vol. 295, no. 12, pp. 1379–1388, 2006.
- A. G. Silva, I. P. Ewald, and M. Sapienza, “Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion,” BMC Cancer, vol. 12, article 237, 2012.
- J. N. Weitzel, J. Clague, A. Martir-Negron, et al., “Prevalence and type of BRCA mutations in Hispanics undergoing genetic cancer risk assessment in the southwestern United States: a report from the Clinical Cancer Genetics Community Research Network,” International Journal of Oncology, vol. 31, no. 2, pp. 210–216, 2013.
- S. Rummel, E. Varner, C. D. Shriver, and R. E. Ellsworth, “Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer,” Breast Cancer Research and Treatment, vol. 137, no. 1, pp. 119–125, 2013.
- E. M. John, A. Miron, G. Gong et al., “Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups,” Journal of the American Medical Association, vol. 298, no. 24, pp. 2869–2876, 2007.
- A. Meindl, “Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population,” International Journal of Cancer, vol. 97, no. 4, pp. 472–480, 2002.
- M. C. B. Gomes, M. M. Costa, R. Borojevic et al., “Prevalence of BRCA1 and BRCA2 mutations in breast cancer patients from Brazil,” Breast Cancer Research and Treatment, vol. 103, no. 3, pp. 349–353, 2007.
- R. M. Dufloth, S. Carvalho, J. K. Heinrich et al., “Analysis of BRCA1 and BRCA2 mutations in Brazilian breast cancer patients with positive family history,” Sao Paulo Medical Journal, vol. 123, no. 4, pp. 192–197, 2005.
- T. Donenberg, J. Lunn, D. Curling et al., “A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas,” Breast Cancer Research and Treatment, vol. 125, no. 2, pp. 591–596, 2011.
- M. Gallardo, A. Silva, L. Rubio et al., “Incidence of BRCA1 and BRCA2 mutations in 54 Chilean families with breast/ovarian cancer, genotype-phenotype correlations,” Breast Cancer Research and Treatment, vol. 95, no. 1, pp. 81–87, 2006.
- M. Akbari, T. Donenberg, J. Lunn, et al., “The Spectrum of BRCA1 and BRCA2 mutations in Breast Cancer Patients in the Bahamas,” Clin Genet, 2013.
- Z. Azeem, A. Farooq, A. K. Naveed, and T. Ahmad, “Breast and ovarian cancer risk due to prevalence of BRCA1 and BRCA2 variants in pakistani population: a Pakistani database report,” Journal of Oncology, vol. 2011, Article ID 632870, 8 pages, 2011.
- M. U. Rashid, A. Zaidi, D. Torres et al., “Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patients,” International Journal of Cancer, vol. 119, no. 12, pp. 2832–2839, 2006.
- N. A. Sharifah, M. I. Nurismah, H. C. Lee et al., “Identification of novel large genomic rearrangements at the BRCA1 locus in Malaysian women with breast cancer,” Cancer Epidemiology, vol. 34, no. 4, pp. 442–447, 2010.
- D. S. C. Lee, S.-Y. Yoon, L. M. Looi et al., “Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients,” Breast Cancer Research, vol. 14, article R61, 2012.
- M. Seong, S. I. Cho, D. Noh et al., “Comprehensive mutational analysis of BRCA1/BRCA2 for Korean breast cancer patients: evidence of a founder mutation,” Clinical Genetics, vol. 76, no. 2, pp. 152–160, 2009.
- S.-H. Han, K.-R. Lee, D.-G. Lee, B.-Y. Kim, K.-E. Lee, and W.-S. Chung, “Mutation analysis of BRCA1 and BRCA2 from 793 Korean patients with sporadic breast cancer,” Clinical Genetics, vol. 70, no. 6, pp. 496–501, 2006.
- D. H. Choi, D. Y. Cho, M. H. Lee et al., “The CHEK2 1100delC mutation is not present in Korean patients with breast cancer cases tested for BRCA1 and BRCA2 mutation,” Breast Cancer Research and Treatment, vol. 112, no. 3, pp. 569–573, 2008.
- H. C. Kang, I.-J. Kim, J.-H. Park et al., “Germline mutations of BRCA1 and BRCA2 in Korean breast and/or ovarian cancer families,” Human Mutation, vol. 20, no. 3, p. 235, 2002.
- N. Ikeda, Y. Miyoshi, K. Yoneda et al., “Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families,” International Journal of Cancer, vol. 91, no. 1, pp. 83–88, 2001.
- M. Matsushima, K. Kobayashi, M. Emi et al., “Mutation analysis of the BRCA1 gene in 76 Japanese ovarian cancer patients: four germline mutations, but no evidence of somatic mutation,” Human Molecular Genetics, vol. 4, no. 10, pp. 1953–1956, 1995.
- W. Chen, K. Pan, T. Ouyang et al., “BRCA1 germline mutations and tumor characteristics in Chinese women with familial or early-onset breast cancer,” Breast Cancer Research and Treatment, vol. 117, no. 1, pp. 55–60, 2009.
- W. Cao, X. Wang, Y. Gao, H. Yang, and J. C. Li, “BRCA1 germ-line mutations and tumor characteristics in eastern Chinese women with familial breast cancer,” The Anatomical Record, vol. 296, no. 2, pp. 273–278, 2013.
- W.-F. Li, Z. Hu, N.-Y. Rao et al., “The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality: two recurrent mutations were identified,” Breast Cancer Research and Treatment, vol. 110, no. 1, pp. 99–109, 2008.
- W. F. Li, Z. Hu, and X. Y. Liu, “BRCA1 germ line mutations in Chinese early-onset breast cancer patients,” Zhonghua Yi Xue Yi Chuan Xue Za Zhi, vol. 24, no. 5, pp. 499–504, 2007.
- A. Kwong, E. K. Ng, and C. L. Wong, “Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis,” PLoS ONE, vol. 7, no. 9, Article ID e43994, 2012.
- U.-S. Khoo, K. Y. K. Chan, A. N. Y. Cheung et al., “Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: a founder mutation of BRCA1 identified in the Chinese population,” Human Mutation, vol. 19, no. 3, pp. 307–308, 2002.
- S. Hedau, N. Jain, S. A. Husain et al., “Novel germline mutations in breast cancer susceptibility genes BRCA1, BRCA2 and p53 gene in breast cancer patients from India,” Breast Cancer Research and Treatment, vol. 88, no. 2, pp. 177–186, 2004.
- K. Vaidyanathan, S. Lakhotia, H. M. Ravishankar, U. Tabassum, G. Mukherjee, and K. Somasundaram, “BRCA1 and BRCA2 germline mutation analysis among Indian women from south India: identification of four novel mutations and high-frequency occurrence of 185delAG mutation,” Journal of Biosciences, vol. 34, no. 3, pp. 415–422, 2009.
- S. Saxena, A. Chakraborty, M. Kaushal et al., “Contribution of germline BRCA1 and BRCA2 sequence alterations to breast cancer in Northern India,” BMC Medical Genetics, vol. 7, article 75, 2006.
- M. T. Valarmathi, M. Sawhney, S. S. V. Deo, N. K. Shukla, and S. N. Das, “Novel germline mutations in the BRCA1 and BRCA2 genes in Indian breast and breast-ovarian cancer families,” Human Mutation, vol. 23, no. 2, p. 205, 2004.
- J. Hansa, R. Kannan, and S. K. Ghosh, “Screening of 185DelAG, 1014DelGT and 3889DelAG BRCA1 mutations in breast cancer patients from North-East India,” Asian Pacific Journal of Cancer Prevention, vol. 13, no. 11, pp. 5871–5874, 2012.
- A. Chakraborty, A. Mukhopadhyay, D. Bhattacharyya, et al., “Frequency of 5382insC mutation of BRCA1 gene among breast cancer patients: an experience from Eastern India,” Familial Cancer, 2012.
- M. S. Anisimenko, D. V. Mitrofanov, O. B. Chasovnikova, M. I. Voevoda, and S. P. Kovalenko, “BRCA1 gene mutations frequency estimation by allele-specific real-time PCR of pooled genomic DNA samples,” Breast, vol. 22, no. 4, pp. 532–536, 2013.
- S. A. Gayther, P. Harrington, P. Russell, G. Kharkevich, R. F. Garkavtseva, and B. A. J. Ponder, “Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia,” American Journal of Human Genetics, vol. 60, no. 5, pp. 1239–1242, 1997.
- O. B. Chasovnikova, D. V. Mitrofanov, M. S. Anisimenko, M. I. Voevoda, S. P. Kovalenko, and V. V. Liakhovich, “Prevalence of mutations BRCA1 5382insC, and CHEK2 1100delC in the population of Siberian region,” Genetika, vol. 48, no. 6, pp. 768–772, 2012.
- I. V. Tereschenko, V. M. Basham, B. A. J. Ponder, and P. D. P. Pharoah, “BRCA1 and BRCA2 mutations in Russian familial breast cancer,” Human Mutation, vol. 19, no. 2, p. 184, 2002.
- A. H. Hashemian, E. Hajizadeh, A. Kazemnejad, M. Atri, and P. Mehdipour, “Penetrance of BRCA1/BRCA2 specific gene mutations in Iranian women with breast cancer,” Saudi Medical Journal, vol. 30, no. 1, pp. 41–44, 2009.
- A. Ghaderi, A. Talei, S. Farjadian, A. Mosalaei, M. Doroudchi, and H. Kimura, “Germline BRCA1 mutations in Iranian women with breast cancer,” Cancer Letters, vol. 165, no. 1, pp. 87–94, 2001.
- V. R. Yassaee, S. Zeinali, and I. Harirchi, “Novel mutations in the BRCA1 and BRCA2 genes in Iranian women with early-onset breast cancer,” Breast Cancer Research, vol. 4, no. 4, p. R6, 2002.
- R. Moslehi, M. H. Kariminejad, V. Ghaffari, and S. Narod, “Analysis of BRCA1 and BRCA2 mutations in an Iranian family with hereditary breast and ovarian cancer syndrome,” American Journal of Medical Genetics, vol. 117, no. 3, pp. 304–305, 2003.
- E. Alvandi, L. Habibi, A. Savabi-E, S. Hosseini Asl, P. Mehdipour, and M. Atri, “Low Frequency of 185delAG founder mutation of BRCA1 gene in Iranian Breast Cancer patients,” Journal of Cancer Molecules, vol. 2, no. 3, pp. 123–127, 2006.
- M. J. Fattahi, Z. Mojtahedi, N. Karimaghaee, A.-R. Talei, S. J. Banani, and A. Ghaderi, “Analysis of BRCA1 and BRCA2 mutations in southern Iranian breast cancer patients,” Archives of Iranian Medicine, vol. 12, no. 6, pp. 584–587, 2009.
- H. Rassi, M. Houshmand, M. Hashemi, K. Majidzadeh, M. H. H. Akbari, and M. S. S. Panahi, “Application of multiplex PCR with histopathologic features for detection of familial breast cancer in formalin-fixed, paraffin-embedded histologic specimens,” Cytology and Genetics, vol. 42, no. 2, pp. 55–62, 2008.
- F. Keshavarzi, G. R. Javadi, and S. Zeinali, “BRCA1 and BRCA2 germline mutations in 85 Iranian breast cancer patients,” Familial Cancer, vol. 11, no. 1, pp. 57–67, 2012.
- L. Quintana-Murci, I. Gal, T. Bakhan et al., “The Tyr978X BRCA1 mutation: occurrence in non-Jewish Iranians and haplotype in French-Canadian and non-Ashkenazi Jews,” Familial Cancer, vol. 4, no. 2, pp. 85–88, 2005.
- Y. Laitman, R. T. Borsthein, D. Stoppa-Lyonnet et al., “Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel,” Breast Cancer Research and Treatment, vol. 127, no. 2, pp. 489–495, 2011.
- H. A. Risch, J. R. McLaughlin, D. E. C. Cole et al., “Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer,” American Journal of Human Genetics, vol. 68, no. 3, pp. 700–710, 2001.
- N. Uhrhammer, A. Abdelouahab, L. Lafarge, V. Feille, A. B. Dib, and Y.-J. Bignon, “BRCA1 mutations in Algerian breast cancer patients: high frequency in young, sporadic cases,” International Journal of Medical Sciences, vol. 5, no. 4, pp. 197–202, 2008.
- R. Bruchim Bar-Sade, A. Kruglikova, B. Modan et al., “The 185delAG BRCA1 mutation originated before the dispersion of Jews in the Diaspora and is not limited to Ashkenazim,” Human Molecular Genetics, vol. 7, no. 5, pp. 801–805, 1998.
- N. C. van der Merwe, N. Hamel, S.-R. Schneider, J. P. Apffelstaedt, J. T. Wijnen, and W. D. Foulkes, “A founder BRCA2 mutation in non-Afrikaner breast cancer patients of the Western Cape of South Africa,” Clinical Genetics, vol. 81, no. 2, pp. 179–184, 2012.
- A. Laraqui, N. Uhrhammer, I. Lahlou-Amine, et al., “Mutation screening of the BRCA1 gene in early onset and familial breast/ovarian cancer in Moroccan population,” International Journal of Medical Sciences, vol. 10, no. 1, pp. 60–67, 2013.
- T. V. O. Hansen, L. Jønson, A. Albrechtsen et al., “Identification of a novel BRCA1 nucleotide 4803delCC/c.4684delCC mutation and a nucleotide 249T>A/c.130T>A (p.Cys44Ser) mutation in two Greenlandic Inuit families: implications for genetic screening of Greenlandic Inuit families with high risk for breast and/or ovarian cancer,” Breast Cancer Research and Treatment, vol. 124, no. 1, pp. 259–264, 2010.
- M. C. Southey, A. A. Tesoriero, C. R. Andersen et al., “BRCA1 mutations and other sequence variants in a population-based sample of Australian women with breast cancer,” British Journal of Cancer, vol. 79, no. 1, pp. 34–39, 1999.
- A. Musolino, M. A. Bella, B. Bortesi et al., “BRCA mutations, molecular markers, and clinical variables in early-onset breast cancer: a population-based study,” Breast, vol. 16, no. 3, pp. 280–292, 2007.
- M. Atri, P. Mehdipour, M. Javidroozi, S. Hosseini-Asl, and E. Jafarimojarrad, “Linking histopathology and family history in breast cancer,” Asian Pacific Journal of Cancer Prevention, vol. 3, no. 1, pp. 33–39, 2002.
- L. C. Collins, A. Martyniak, M. J. Kandel et al., “Basal cytokeratin and epidermal growth factor receptor expression are not predictive of BRCA1 mutation status in women with triple-negative breast cancers,” American Journal of Surgical Pathology, vol. 33, no. 7, pp. 1093–1097, 2009.
- E. Thirthagiri, S. Y. Lee, P. Kang et al., “Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer,” Breast Cancer Research, vol. 10, no. 4, article R59, 2008.
- B. Davarnia, P. Mehdipour M, S. Atri, and Hosseini-Asl, “Investigation on the correlation between BRCA1 gene expression and the pathologic statue of breast tumors,” Magazine of Ardebil University of Medical Sciences, vol. 12, no. 2, pp. 132–139, 2012.
- M. R. Stratton, “Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases,” Lancet, vol. 349, no. 9064, pp. 1505–1510, 1997.
- A. M. Gonzalez-Angulo, K. M. Timms, S. Liu et al., “Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer,” Clinical Cancer Research, vol. 17, no. 5, pp. 1082–1089, 2011.
- L. D. Smith, A. A. Tesoriero, E. M. Wong et al., “Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry,” Breast Cancer Research, vol. 13, no. 1, article R14, 2011.
- V. Bonadona, S. Dussart-Moser, N. Voirin et al., “Prognosis of early-onset breast cancer based on BRCA1/2 mutation status in a French population-based cohort and review,” Breast Cancer Research and Treatment, vol. 101, no. 2, pp. 233–245, 2007.
- N. Hamel, B.-J. Feng, L. Foretova et al., “On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations,” European Journal of Human Genetics, vol. 19, no. 3, pp. 300–306, 2011.
- J. Hartikainen, V. Kataja, M. Pirskanen et al., “Screening for BRCA1 and BRCA2 mutations in Eastern Finnish breast/ ovarian cancer families,” Clinical Genetics, vol. 72, no. 4, pp. 311–320, 2007.
- A. Peixoto, C. Santos, P. Rocha et al., “The c.156-157insAlu BRCA2 rearrangement accounts for more than one-fourth of deleterious BRCA mutations in northern/central Portugal,” Breast Cancer Research and Treatment, vol. 114, no. 1, pp. 31–38, 2009.
- F. Schoumacher, A. Glaus, H. Mueller, U. Eppenberger, B. Bolliger, and H. J. Senn, “BRCA1/2 mutations in Swiss patients with familial or early-onset breast and ovarian cancer,” Swiss Medical Weekly, vol. 131, no. 15-16, pp. 223–226, 2001.
- S. L. Neuhausen, A. K. Godwin, R. Gershoni-Baruch et al., “Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study,” American Journal of Human Genetics, vol. 62, no. 6, pp. 1381–1388, 1998.
- A. Liede, B. Cohen, D. M. Black et al., “Evidence of a founder BRCA1 mutation in Scotland,” British Journal of Cancer, vol. 82, no. 3, pp. 705–711, 2000.
- U. Hamann, X. Liu, N. Bungardt, H. Ulrich Ulmer, G. Bastert, and H.-P. Sinn, “Similar contributions of BRCA1 and BRCA2 germline mutations to early-onset breast cancer in Germany,” European Journal of Human Genetics, vol. 11, no. 6, pp. 464–467, 2003.
- U. Hamann, M. Häner, U. Stosiek, G. Bastert, and R. J. Scott, “Low frequency of BRCA1 germline mutations in 45 German breast/ovarian cancer families,” Journal of Medical Genetics, vol. 34, no. 11, pp. 884–888, 1997.
- U. Hamann, H. Brauch, A. M. Garvin, G. Bastert, and R. J. Scott, “German family study on hereditary breast and/or ovarian cancer: germline mutation analysis of the BRCA1 gene,” Genes Chromosomes Cancer, vol. 18, no. 2, pp. 126–132, 1997.
- H. Vézina, F. Durocher, M. Dumont et al., “Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families,” Human Genetics, vol. 117, no. 2-3, pp. 119–132, 2005.
- K. Oros, G. Leblanc, S. Arcand et al., “Haplotype analysis suggest common founders in carriers of the recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families,” BMC Medical Genetics, vol. 7, article 23, 2006.
- J. Simard, M. Dumont, A.-M. Moisan et al., “Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer,” Journal of Medical Genetics, vol. 44, pp. 107–121, 2007.
- D. Muller, C. Bonaiti-Pellié, J. Abecassis, D. Stoppa-Lyonnet, and J.-P. Fricker, “BRCA1 testing in breast and/or ovarian cancer families from northeastern France identifies two common mutations with a founder effect,” Familial Cancer, vol. 3, no. 1, pp. 15–20, 2004.
- S. Gad, V. Caux-Moncoutier, S. Pagès-Berhouet et al., “Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families,” Oncogene, vol. 21, no. 44, pp. 6841–6847, 2002.
- M. A. Caligo, C. Ghimenti, G. Cipollini et al., “BRCA1 germline mutational spectrum in Italian families from Tuscany: a high frequency of novel mutations,” Oncogene, vol. 13, no. 7, pp. 1483–1488, 1996.
- K. Claes, E. Machackova, X. De Vos, B. Poppe, A. De Paepe, and L. Messiaen, “Mutation analysis of the BRCA1 and BRCA2 genes in the Belgian patient population and identification of a Belgian founder mutation BRCA1 IVS5 + 3 A > G,” Disease Markers, vol. 15, no. 1–3, pp. 69–73, 1999.
- K. Claes, B. Poppe, I. Coene, A. De Paepe, and L. Messiaen, “BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families,” British Journal of Cancer, vol. 90, no. 6, pp. 1244–1251, 2004.
- P. Pohlreich, M. Zikan, J. Stribrna et al., “High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area,” Breast Cancer Research, vol. 7, no. 5, pp. R728–R736, 2005.
- S. Čierniková, M. Tomka, M. Kováč, V. Števurková, and V. Zajac, “Ashkenazi founder BRCA1/BRCA2 mutations in Slovak hereditary breast and/or ovarian cancer families,” Neoplasma, vol. 53, no. 2, pp. 97–102, 2006.
- M. Konecny, M. Vizvaryova, E. Weismanova et al., “The spectrum and incidence of BRCA1 pathogenic mutations in Slovak breast/ovarian cancer families,” Neoplasma, vol. 54, no. 2, pp. 137–142, 2007.
- M. Konecny, M. Milly, K. Zavodna et al., “Comprehensive genetic characterization of hereditary breast/ovarian cancer families from Slovakia,” Breast Cancer Research and Treatment, vol. 126, no. 1, pp. 119–130, 2011.
- M. Konecny, M. Vizvaryova, K. Zavodna et al., “Identification of a novel mutations Brca1*c.80 + 3del4 and Brca2*c.6589delA in Slovak HBOC families,” Breast Cancer Research and Treatment, vol. 119, no. 1, pp. 233–237, 2010.
- C. Koumpis, C. Dimitrakakis, A. Antsaklis et al., “Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Greece,” Hereditary Cancer in Clinical Practice, vol. 9, p. 10, 2011.
- T. M. Wagner, R. A. Moslinger, and D. Muhr, “BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics,” International Journal of Cancer, vol. 77, no. 3, pp. 354–360, 1998.
- B. Csokay, L. Tihomirova, A. Stengrevics, O. Sinicka, and E. Olah, “Strong founder effects in BRCA1 mutation carrier breast cancer patients from Latvia. Mutation in brief no. 258. Online,” Human Mutation, vol. 14, no. 1, p. 92, 1999.
- L. Tikhomirova, O. Sinicka, D. Smite, J. Eglitis, S. V. Hodgson, and A. Stengrevics, “High prevalence of two BRCA1 mutations, 4154delA and 5382insC, in Latvia,” Familial Cancer, vol. 4, no. 2, pp. 77–84, 2005.
- M. Van Der Looij, C. Szabo, I. Besznyak et al., “Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary,” International Journal of Cancer, vol. 86, no. 5, pp. 737–740, 2000.
- S. J. Ramus, Z. Kote-Jarai, L. S. Friedman et al., “Analysis of BRCA1 and BRCA2 mutations in hungarian families with breast or breast-ovarian cancer,” American Journal of Human Genetics, vol. 60, no. 5, pp. 1242–1246, 1997.
- J. Papp, L. Raicevic, J. Milasin, B. Dimitrijevic, S. Radulovic, and E. Olah, “Germline mutation analysis of BRCA1 and BRCA2 genes in Yugoslav breast/ovarian cancer families,” Oncology Reports, vol. 6, no. 6, pp. 1435–1438, 1999.
- N. V. Bogdanova, N. N. Antonenkova, Y. I. Rogov, J. H. Karstens, P. Hillemanns, and T. Dörk, “High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus,” Clinical Genetics, vol. 78, no. 4, pp. 364–372, 2010.
- R. C. Rodriguez, A. A. Esperon, R. Ropero et al., “Prevalence of BRCA1 and BRCA2 mutations in breast cancer patients from Cuba,” Familial Cancer, vol. 7, no. 3, pp. 275–279, 2008.
- G. Gutierrez Espeleta, M. Llacuachaqui, L. Garcia-Jimenez, et al., “BRCA1 and BRCA2 mutations among familial breast cancer patients from Costa Rica,” Clinical Genetics, vol. 82, no. 5, pp. 484–488, 2012.
- D. M. Carraro, M. A. Koike Folgueira, B. C. Garcia Lisboa et al., “Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil,” PLoS ONE, vol. 8, no. 3, Article ID e57581, 2013.
- A. O. Rodríguez, M. Llacuachaqui, G. G. Pardo et al., “BRCA1 and BRCA2 mutations among ovarian cancer patients from Colombia,” Gynecologic Oncology, vol. 124, no. 2, pp. 236–243, 2012.
- K. Lara, N. Consigliere, J. Perez, and A. Porco, “BRCA1 and BRCA2 mutations in breast cancer patients from Venezuela,” Biological Research, vol. 45, no. 2, pp. 117–130, 2012.
- J. Dutil, J. L. Colon-Colon, J. L. Matta, R. Sutphen, and M. Echenique, “Identification of the prevalent BRCA1 and BRCA2 mutations in the female population of Puerto Rico,” Cancer Genetics, vol. 205, no. 5, pp. 242–248, 2012.
- F. Vaca-Paniagua, R. M. Alvarez-Gomez, V. Fragoso-Ontiveros, et al., “Full-exon pyrosequencing screening of BRCA germline mutations in Mexican women with inherited breast and ovarian cancer,” PLoS ONE, vol. 7, no. 5, Article ID e37432, 2012.
- H. Yazici, O. Bitisik, E. Akisik et al., “BRCA1 and BRCA2 mutations in Turkish breast/ovarian families and young breast cancer patients,” British Journal of Cancer, vol. 83, no. 6, pp. 737–742, 2000.
- A. Balci, P. Huusko, K. Pääkkönen et al., “Mutation analysis of BRCA1 and BRCA2 in Turkish cancer families: a novel mutation BRCA2 3414del4 found in male breast cancer,” European Journal of Cancer, vol. 35, no. 5, pp. 707–710, 1999.
- H. Özdag, M. Tez, I. Sayek et al., “Germ line BRCA1 and BRCA2 gene mutations in Turkish breast cancer patients,” European Journal of Cancer, vol. 36, no. 16, pp. 2076–2082, 2000.
- B. H. Son, S. H. Ahn, S.-W. Kim et al., “Prevalence of BRCA1 and BRCA2 mutations in non-familial breast cancer patients with high risks in Korea: the Korean Hereditary Breast Cancer (KOHBRA) Study,” Breast Cancer Research and Treatment, vol. 133, no. 3, pp. 1143–1152, 2012.
- J.-H. Jang, J. E. Lee, M.-J. Kwon et al., “Spectra of BRCA1 and BRCA2 mutations in Korean patients with breast cancer: The importance of whole-gene sequencing,” Journal of Human Genetics, vol. 57, pp. 212–215, 2012.
- X. Zhi, C. Szabo, S. Chopin et al., “BRCA1 and BRCA2 sequence variants in Chinese breast cancer families,” Human Mutation, vol. 20, no. 6, p. 474, 2002.
- S.-T. Chen, R.-A. Chen, S.-J. Kuo, and Y.-C. Chien, “Mutational screening of breast cancer susceptibility gene 1 from early onset, bi-lateral, and familial breast cancer patients in Taiwan,” Breast Cancer Research and Treatment, vol. 77, no. 2, pp. 133–143, 2003.
- P. Patmasiriwat, K. Bhothisuwan, O. M. Sinilnikova et al., “Analysis of breast cancer susceptibility genes BRCA1 and BRCA2 in Thai familial and isolated early-onset breast and ovarian cancer,” Human Mutation, vol. 20, no. 3, p. 230, 2002.
- W.-H. Kuo, P.-H. Lin, A.-C. Huang et al., “Multimodel assessment of BRCA1 mutations in Taiwanese (ethnic Chinese) women with early-onset, bilateral or familial breast cancer,” Journal of Human Genetics, vol. 57, no. 2, pp. 130–138, 2012.
- S. S.-L. Li, H.-M. Tseng, T.-P. Yang et al., “Molecular characterization of germline mutations in the BRCA1 and BRCA2 genes from breast cancer families in Taiwan,” Human Genetics, vol. 104, no. 3, pp. 201–204, 1999.
- Y. K. Lim, P. T. C. Iau, A. B. Ali et al., “Identification of novel BRCA large genomic rearrangements in Singapore Asian breast and ovarian patients with cancer,” Clinical Genetics, vol. 71, no. 4, pp. 331–342, 2007.
- J.-H. Sng, A. B. Ali, S. C. Lee et al., “BRCA1 c.2845insA is a recurring mutation with a founder effect in Singapore Malay women with early onset breast/ovarian cancer,” Journal of Medical Genetics, vol. 40, no. 10, article e117, 2003.
- A. S. G. Lee, G. H. Ho, P. C. Oh et al., “Founder mutation in the BRCA1 gene in Malay breast cancer patients from Singapore,” Human Mutation, vol. 22, no. 2, p. 178, 2003.
- M. L. De Leon Matsuda, A. Liede, E. Kwan et al., “BRCA1 and BRCA2 mutations among breast cancer patients from the Philippines,” International Journal of Cancer, vol. 98, no. 4, pp. 596–603, 2002.
- N. Jalkh, J. Nassar-Slaba, E. Chouery et al., “Prevalance of BRCA1 and BRCA2 mutations in familial breast cancer patients in Lebanon,” Hereditary Cancer in Clinical Practice, vol. 10, no. 1, p. 7, 2012.
- M. T. Valarmathi, M. T. A. A, S. S. Deo, N. K. Shukla, and S. N. Das, “BRCA1 germline mutations in Indian familial breast cancer,” Human Mutation, vol. 21, no. 1, pp. 98–99, 2003.
- D. Purnomosari, G. Pals, A. Wahyono et al., “BRCA1 and BRCA2 germline mutation analysis in the Indonesian population,” Breast Cancer Research and Treatment, vol. 106, no. 2, pp. 297–304, 2007.
- O. Ginsburg, N. Dinh, T. To et al., “Family history, BRCA mutations and breast cancer in Vietnamese women,” Clinical Genetics, vol. 80, no. 1, pp. 89–92, 2011.
- S. S. Ibrahim, E. E. Hafez, and M. M. Hashishe, “Presymptomatic breast cancer in Egypt: role of BRCA1 and BRCA2 tumor suppressor genes mutations detection,” Journal of Experimental and Clinical Cancer Research, vol. 29, no. 1, article 82, 2010.
- W. Troudi, N. Uhrhammer, C. Sibille et al., “Contribution of the BRCA1 and BRCA2 mutations to breast cancer in Tunisia,” Journal of Human Genetics, vol. 52, no. 11, pp. 915–920, 2007.
- W. Troudi, N. Uhrhammer, K. B. Romdhane et al., “Complete mutation screening and haplotype characterization of BRCA1 gene in Tunisian patients with familial breast cancer,” Cancer Biomarkers, vol. 4, no. 1, pp. 11–18, 2008.
- A. Tazzite, H. Jouhadi, S. Nadifi et al., “BRCA1 and BRCA2 germline mutations in Moroccan breast/ovarian cancer families: novel mutations and unclassified variants,” Gynecologic Oncology, vol. 125, no. 3, pp. 687–692, 2012.