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Gastroenterology Research and Practice
Volume 2016, Article ID 2139489, 10 pages
http://dx.doi.org/10.1155/2016/2139489
Review Article

Single Nucleotide Polymorphisms as Prognostic and Predictive Factors of Adjuvant Chemotherapy in Colorectal Cancer of Stages I and II

1University Medical Centre Maribor, 2000 Maribor, Slovenia
2Faculty of Medicine, Centre for Human Molecular Genetics and Pharmacogenomics, University of Maribor, 2000 Maribor, Slovenia
3Faculty for Chemistry and Chemical Engineering, Laboratory for Biochemistry, Molecular Biology and Genomics, University of Maribor, 2000 Maribor, Slovenia
4University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia

Received 24 July 2015; Accepted 11 November 2015

Academic Editor: Masood A. Shammas

Copyright © 2016 Matej Horvat et al. 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.

Abstract

Colorectal cancer (CRC) is a highly heterogeneous disease regarding the stage at time of diagnosis and there is special attention regarding adjuvant chemotherapy in unselected patients with stage I and stage II. The clinicohistologically based TNM staging system with emphasis on histological evaluation of primary tumor and resected regional lymph nodes remains the standard of staging, but it has restricted sensitivity resulting in false downward stage migration. Molecular characteristics might predispose tumors to a worse prognosis and identification of those enables identifying patients with high risk of disease recurrence. Suitable predictive markers also enable choosing the most appropriate therapy. The current challenge facing adjuvant chemotherapy in stages I and II CRC is choosing patients with the highest risk of disease recurrence who are going to derive most benefit without facing unnecessary adverse effects. Single nucleotide polymorphisms (SNPs) are one of the potential molecular markers that might help us identify patients with unfavorable prognostic factors regarding disease initiation and recurrence and could determine selection of an appropriate chemotherapy regimen in the adjuvant and metastatic setting. In this paper, we discuss SNPs of genes involved in the multistep processes of cancerogenesis, metastasis, and the metabolism of chemotherapy that might prove clinically significant.

1. Introduction

Colorectal cancer (CRC) represents the third most common malignancy worldwide in men and the second most common malignancy in women, accounting for approximately 10% of all tumor types worldwide and 8% of cancer related mortality [1]. With the advance in specific oncological treatment and earlier diagnosis due to screening programs, 5-year survival rates in CRC have risen from 56,5% for patients diagnosed in the early 1980s to 63,2% for those diagnosed in the early 1990s and most recently to 64,9% for those diagnosed after 2000 [2].

CRC is a highly heterogeneous disease regarding the stage at time of diagnosis. Approximately 15% will have node-negative, localized, stage I disease (T1-T2, N0, M0), 25% will have node-negative, locally more advanced stage II disease (T3-T4, N0, M0), 35% will have node-positive stage III disease (any T, N1-2, M0), and 25% will have advanced stage IV disease (any T, any N, M1) [3]. With surgery alone, the overall survival at 5 years for unselected patients with stage II is about 80%, with adjuvant chemotherapy offering a minimal incremental benefit in survival of less than 5%. For patients with stage III survival with surgery alone, the overall survival rate is approximately 50%. The difference in survival with all treatment modalities is highly different between stages, with 90,8% for localized disease of stages I and II, 69,5% for stage III, and 11,3% for stage IV [4].

The current treatment for resectable CRC of stages I, II, and III is surgical resection. For patients of stage I, surgical resection is the only recommended treatment without adjuvant chemotherapy. For patients of stage III, adjuvant chemotherapy is recommended for every patient. In contrast, for patients of stage II, adjuvant chemotherapy is not recommended for unselected patients [57]. Even though stage I and early stage II CRC are prognostically very favorable, with a small burden of disease, a proportion of these tumors have certain characteristics, making them clinically more malignant and therefore predisposing them to disease recurrence or metachronous colon cancer [8].

Single nucleotide polymorphisms (SNPs) represent a useful biomarker with the potential of being a prognostic and/or predictive factor for everyday clinical practice and decision making, but it is necessary to discover which out of nearly 150 million SNPs in the human genome have clinical significance either influencing the risk of CRC incidence, or disease dissemination, or influencing chemotherapy metabolism and thereby efficiency and side effects. We discuss in our review several SNPs that are potential prognostic factors in the adjuvant setting, because they are more frequent in metastatic disease. We also discuss several SNPs that are potential predictive factors, because of their role in chemotherapy metabolism and thereby influence on efficiency and incidence of adverse effects.

2. Prognostic Factors in Colorectal Cancer

There is special attention and controversy regarding stage I and stage II disease. Stage II especially is a highly heterogeneous disease, with 5-year survival of stage IIA patients being approximately 87,5% and stage IIC approximately 58,4% [9]. Out of 40% of CRC patients with pathological-negative lymph nodes by current methods of analysis (pN0), up to 30% of patients with stage I and up to 50% of patients with stage II disease will develop metastatic disease during the course of their follow-up. Furthermore, metastatic disease is present in 25% of CRC patients at the time of diagnosis and another 20–30% of patients with stages I, II, and III are going to develop metastasis after potentially curable surgical treatment, meaning that altogether up to 50% of CRC patients will eventually develop metastases [10].

Even with the advent of new chemotherapy regimens and targeted therapies, only potential curative treatment for metastatic disease is surgery in selected patients with liver metastases [11]. It is therefore important to identify patients with micrometastasis that are potentially curable. Identification of suitable prognostic markers enables clinicians to identify patients with a high risk of disease recurrence and identification of suitable predictive markers enables clinicians to choose the most appropriate adjuvant therapy [12].

Potential clinical and pathological risk factors for recurrence of stage II CRC have been investigated and incorporated in different guidelines, but a definite consensus has not yet been reached. According to European and American guidelines (The European Society for Medical Oncology (ESMO), The American Society of Clinical Oncology (ASCO), and The National Comprehensive Cancer Network (NCCN)), negative prognostic risk factors according to all three sets of guidelines are T4 tumors, bowel perforation, inadequately sampled lymph nodes, and poorly differentiated histology. Further negative prognostic markers included in one or two sets of guidelines are bowel obstruction, lymphovascular invasion, perineural invasion, and indeterminate or positive margins [57].

Prognostic significance as pathological risk factors in CRC may also have tumor budding, modified classical grading system, lymphocytic infiltration, and circumferential margin involvement [1316]. Tumor budding is an independent marker of a potentially poor outcome in CRC, but there is a lack of uniformity regarding tumor budding [17]. It is defined as presence of individual tumor cells and clusters of tumor cells at the invasive front of the tumor and it has been postulated to represent an epithelial-mesenchymal transition, a critical mechanism for the acquisition of malignant phenotypes [18]. Another promising pathohistological feature is the modified classical grading system according to WHO. The grading system currently in use does not encompass rare subtypes of CRC and is subject to interobserver variability. A novel grading system was recently proposed: the poorly differentiated clusters. It is defined by counting clusters composed of 5 or more cancer cells and lacking a gland-like structure [15]. Circumferential margin involvement is especially important in rectal cancer and is a strong predictor for local recurrence after surgery when associated with a margin of less than 2 mm, but it also presents with an increased risk of distant metastases with margins of less than 1 mm [16].

Possible new prognostic and predictive factors emerging in CRC are due to immunological properties next to classical TNM classification. A worldwide task force has researched immunological characteristics of the tumor and translated them into “immunoscore.” Two lymphocyte populations (CD8 and CD45RO) were evaluated in the center of the tumor and invasive margin and graded accordingly to its density. It was discovered that patients with higher lymphocytic densities had a statistically lower relapse rate [19].

The most important prognostic marker of resectable CRC survival is still regional lymph node involvement; however, this is greatly influenced by the number of lymph nodes resected by the surgeon and by the number of lymph nodes examined by the pathologist. The clinicohistologically based TNM staging system with emphasis on histological evaluation of primary tumor and regional resected lymph nodes remains the standard of staging, but imprecision reflects its limitations. Microscopy has restricted sensitivity with normal detection limits of one cancer cell in about 200 [20]. Histology typically reviews less than 0,1% of biopsied tissue producing a sampling error, as more than 99,9% of available tissue is not examined. Another limitation is inhomogeneous distribution of cancer cells in biopsied tissue, which may produce a substantial amount of false-negative results regarding regional lymph node status resulting in false-negative downward stage migration. These inadequacies can be overcome by molecular staging with molecular detection of occult lymph node metastasis producing an independent indicator of prognostic risk of CRC recurrence [21].

3. Adjuvant Chemotherapy in Colorectal Cancer

Adjuvant chemotherapy is the standard treatment in stage III CRC being introduced into everyday clinical practice in the early 1990s, first as a combination of 5-FU and levamisole administered for 12 months and later 6 months of therapy with the same survival benefit [22]. Oral capecitabine has also proven to be equivalent to intravenous 5-FU plus leucovorin [23]. In 2004, oxaliplatin in combination with 5-FU was proven to be superior to 5-FU/LV and was approved as a standard regimen for adjuvant chemotherapy in stage III CRC with an absolute benefit of 8% to 10% [24, 25]. Also, the combination of oxaliplatin with capecitabine, a 5-FU prodrug, has also proven to be superior to 5-FU/LV and equivalent to a combination of oxaliplatin and 5-FU in terms of efficiency [26]. Systemic treatment of CRC in the metastatic setting has been extensively modified in the last decade, but in the adjuvant setting only 5-FU and its prodrug capecitabine either as monotherapy or in combination with oxaliplatin have a statistically significant effect on overall survival. No benefit of targeted therapy or irinotecan in unselected patients has been observed [27, 28].

For stage I CRC, according to clinical practice guidelines, wide surgical resection with formation of anastomosis is the treatment of choice. Adjuvant chemotherapy is not required [57].

Adjuvant chemotherapy in stage II remains much more controversial. In the QUASAR study, chemotherapy with 5-FU and oxaliplatin improved survival in unselected stage II patients by merely 3,6%. Also the number of resected lymph nodes was inadequate (less than 12) in a proportion of patients, making it probable that the stage was underestimated [29]. Other pooled retrospective analyses also showed conflicting results. One analysis suggested an approximate 8% absolute reduction in mortality, whereas a similar analysis showed no benefit from adjuvant chemotherapy [30, 31]. A meta-analysis published in 2012 showed a benefit with adjuvant chemotherapy in stage II colon cancer patients, but the trials used various chemotherapy regimens. There was also lack of surgical quality control and the reported differences were small [32]. There is also the question of adding oxaliplatin to fluoropyrimidine backbone with stage II CRC patients. Results from the C-07 trials did not show a benefit of adding oxaliplatin in adjuvant chemotherapy for stage II patients regarding overall survival, but a hint of benefit regarding disease free survival [33]. It remains uncertain whether patients with stage II CRC derive sufficient benefit from adjuvant chemotherapy [34]. Adjuvant treatment is recommended for all patients with stage III disease and taken altogether stage IIIA disease (T1-2, N1) appears to be associated with statistically significantly improved survival compared with that of stage IIC disease [35]. Adjuvant chemotherapy in stage II CRC is recommended for selected patients with clinical or pathological risk factors. The problem is that these risk factors differ according to different clinical treatment guidelines. Consensus on them has not been reached yet. There is no clear message regarding adjuvant chemotherapy patient selection in stage II CRC [57].

Regional lymph node status regarding infiltration with cancer cells is at the moment the most important prognostic factor in several solid tumors, but patients with node-negative disease are still at a significant risk of disease recurrence and development of distant metastasis making the development of a more accurate staging system based on either molecular or immunological characteristics of patient and tumor of paramount importance [36]. Histologically identical tumors may have a drastically different prognosis and/or response to treatment and these discoveries prompted the theory that, rather than a single malignancy, CRC is a heterogeneous, multifactorial disease and that individual tumors are initiated and progress in a unique manner, which is not necessarily identical amongst all tumors. As a result of this, CRC research is shifting from a clinical and pathohistological perspective towards developing an understanding of the molecular basis of this malignancy, including individual susceptibility, development, progression response, and resistance to antitumor treatment and metastatic spread [37].

4. Molecular Prognostic Factors in Resectable Colorectal Cancer

Patients and physicians are on a daily basis confronted with choices about whether to embark on a course of adjuvant chemotherapy designed to eliminate micrometastatic disease after potentially curative surgical treatment, or whether not to administer treatment and which treatment to choose. In elderly patients aged more than 70 years and in patients with comorbidities, the importance of choosing an appropriate regimen with acceptable toxicity is of special importance, as these patients may not be as robust as their younger counterparts and patients with no comorbidities and because they may place a different value on the time and logistical challenges relevant to a course of a treatment [38].

Molecular mechanisms regulating cancer progression in solid tumors encompass genomic, transcriptome, and epigenetic alterations. The latter significantly contribute to tumor progression particularly in early stage metastasis, in which acquisition of epigenetic alterations of involvement of epigenetic factors may allow cancer cells to disseminate from the primary tumor and metastasize to and survive at a distant site [39]. Growing evidence supports the idea that epithelial cancers including CRC are diseases driven by pluripotent, self-renewing cancer stem cells, which are chemotherapy resistant, and that this is one of the primary causes for tumor recurrence [40].

The most prominent molecular predictive marker in CRC is the KRAS mutation identifying 40% of patients that will not respond to anti-EGFR treatment with cetuximab or panitumumab. Nonetheless, it has no significance in the adjuvant setting as targeted therapies did not show any clinical benefit [41]. A molecular characteristic important in the adjuvant setting is microsatellite instability (MSI-H), being a favorable prognostic factor in all disease stages in comparison to microsatellite stable tumors (MSS) [42]. Besides being a favorable prognostic marker, it also seems to predispose chemoresistance to 5-FU-based chemotherapy, thereby representing a negative predictive marker in the adjuvant CRC setting [43]. Both of these facts make MSI-H patients less suitable candidates for adjuvant chemotherapy. The recent ESMO clinical practice guidelines suggest testing for MSI-H in stage II colon cancer in order to contribute in treatment decision making regarding chemotherapy administration [44]. The role of oxaliplatin-based therapy is still being evaluated in the MSI-H setting [45]. There might even be a role for irinotecan-based therapy in MSI-H patients in the adjuvant setting [46].

High penetrance mutations, such as those of APC and MMR genes, account for less than 5% of cases in the pathogenesis of CRC [47, 48]. Another 8,3% of cases arise in families with two affected first- or second-degree relatives with mildly or moderately penetrating alleles explaining the familial aggregation. The remaining proportion of inherited susceptibility that is as high as −35% as discovered by twin studies is likely to be explained by low-risk variants that can also depend on several parameters in any given population (mutation rate, genetic selection, and population demography) thereby conferring risk in one population, but not in another [49, 50].

5. Single Nucleotide Polymorphisms in Resectable Colorectal Cancer

Genome-wide association studies (GWAS) enable us to examine many common genetic variants in different individuals thereby discovering if any variant is associated with a trait as predisposition to developing cancer. SNP is a DNA sequence variation occurring within a population with an inhomogeneous distribution, occurring more frequently in noncoding regions with other factors such as genetic recombination and mutation rate determining SNP density [51].

There are two different types of SNPs influencing incidence of diseases. If the variation of the SNP is located within or close to the translated region, any amino acid substitutions that alter protein synthesis could be directly connected to the disease with a straightforward correlation. On the other hand, if a disease-associated SNP is located in a noncoding region or there is no gene near the SNP, then it is more difficult to determine the mechanism by which the SNP is associated with the disease [52]. A significant factor of heterogenous distribution is microsatellites, in particular, AT microsatellites being a potent predictor of reduced SNP density [53]. The GWAS approach has proved powerful in identifying robust associations between many SNPs and traits, but additional work is needed to determine the functional basis for the observed associations [54].

Several studies regarding CRC incidence have been conducted in the last decade, but our special interest is on studies regarding germline SNPs that may prove to be important in the CRC adjuvant chemotherapy setting. SNPs are characteristics of genes that may in certain cases be regarded as negative prognostic factors and may predispose patients to disease recurrence.

5.1. Single Nucleotide Polymorphisms as a Predictive Marker

SNPs can be predictive markers in CRC therapy, because of their role in genetic pathways involved in metabolism, cellular transport, and the mechanisms of action of chemotherapy agents. They can thereby influence response to treatment [55]. As aforementioned, the standard adjuvant chemotherapy is 5-FU or its prodrug capecitabine as monotherapy or a combination of 5-FU or capecitabine with oxaliplatin (FOLFOX or XELOX regimen). Identical chemotherapy regimen is one of the standard chemotherapy regimens in metastatic CRC [56].

Several pharmacogenetic studies were conducted regarding response to treatment with oxaliplatin and 5-FU. Polymorphisms ERCC2 Lys751Gln and XRCC1 Arg399Gln showed worse response and shorter survival to chemotherapy. Both studies were conducted in the advanced CRC setting with either FOLFOX or XELOX regimen [57, 58]. Ye et al. [59] conducted a meta-analysis concerning XRCC1 and GSTP1 polymorphisms and prognosis with oxaliplatin-based chemotherapy in metastatic CRC. XRCC1 Arg399Gln polymorphism was significantly associated with oxaliplatin-based chemotherapy response in CRC when stable disease and disease progression were defined as nonresponse, although the association was not significant when only disease progression was considered as nonresponse. The tumor response rate was significantly lower in patients who carried Arg/Gln or Gln/Gln genotypes. The present meta-analysis did not show a significant relationship between tumor response and GSTP1 polymorphisms. In clinical studies performed in advanced colorectal setting with oxaliplatin/5-FU-based chemotherapy regimens, polymorphisms GSTP1 Ile105Val, MGMT −535G/T, MTHFR 677C/T, and MTHFR 1298A/C showed longer time to progression or longer survival [6063]. Studies performed in the adjuvant CRC setting have also discovered a predictive role of SNPs. Cecchin et al. [64] conducted a study concerning MTHFR 1298A>C (rs1801131) polymorphism as a predictor of survival in two cohorts of stage II/III setting of CRC patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin. MTHFR 1298CC genotype carriers had worse disease free survival and also worse overall survival in both cohorts. They concluded MTHFR 1298A>C is a prognostic factor that could be an additional criterion for the choice of a proper adjuvant regimen in the adjuvant setting. Kap et al. [65] conducted a study concerning genetic variants in the glutathione S-transferase (GST) genes and survival in CRC patients after chemotherapy and differences according to treatment with oxaliplatin. Patients with stages II–IV were included. CRC patients who were homozygote carriers of GSTM1 had significantly poorer survival after treatment with oxaliplatin than those not treated with oxaliplatin. The association was significant in metastatic CRC patients treated with oxaliplatin. Neither the GSTP1 105Val allele nor the GSTT1 deletion was significantly associated with CRC survival. These data suggest that GSTM1 may be a predictive marker for oxaliplatin therapy. Absenger et al. [66] conducted a study concerning cyclin D1 (CCND1) rs9344 G>A polymorphism predicting clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy in stage II/III. Patients treated with 5-FU-based chemotherapy carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence. In the validation set, the A allele of CCND1 SNP rs9344 remained significantly associated with decreased time-to-tumor recurrence. They concluded that CCND1 rs9344 may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients. Páez et al. [67] conducted a study concerning association of common gene variants in the Wnt/β-catenin pathway in colon cancer recurrence. They investigated germline polymorphisms in a panel of Wnt/β-catenin pathway genes to predict time-to-tumor recurrence in patients with high risk stage II and stage III. They discovered that the minor allele of WNT5B SNP rs2010851 was significantly associated with shorter time-to-tumor recurrence in high risk stage II patients.

Another factor in addition to treatment response is evaluating the effect of SNPs on chemotherapy toxicity. Chemotherapy adverse effects are neither stage nor disease specific. Chemotherapy regimens used in different cancers produce similar adverse effects. As well as being a predictive factor of treatment efficiency, SNPs are also predictive factors of adverse effect incidence. Caronia et al. [68] discovered an association of increased risk of hand-foot syndrome appearance with SNP rs532545 in the CDA gene in CRC and breast cancer patients either in the adjuvant or metastatic setting. Gusella et al. [69] discovered that MTHFR C677T polymorphism was protective against grade 3 and 4 toxicity in CRC patients of B2 and C Dukes stages receiving adjuvant chemotherapy with 5-FU. Argyriou et al. [70] discovered an association regarding voltage-gated sodium channel polymorphisms in the development of oxaliplatin-induced peripheral neurotoxicity in CRC patients in either the adjuvant or metastatic setting. SNPs SCN4A-rs2302237 and SCN10A-rs1263292 emerged as being significantly associated with an increased incidence of acute oxaliplatin-induced peripheral neuropathy. SCN4A-rs2302237 emerged also as being predictive of the clinical severity of acute oxaliplatin-induced peripheral neuropathy and the occurrence of cumulative/chronic oxaliplatin-induced peripheral neuropathy. Custodio et al. [71] discovered that cyclin H (CCNH) rs2230641 C/C and the ATP-binding cassette subfamily G, member 2 (ABCG2) rs3114018 A/A, were associated with a higher risk of severe oxaliplatin-induced peripheral neuropathy in patients with stage II and III CRC. Patients harboring the combination of both genotypes had a higher risk of grades 2-3 oxaliplatin-induced peripheral neuropathy.

5.2. Single Nucleotide Polymorphisms as a Prognostic Marker

Metastasis is a multistep process with many genes regulating escape from the primary colorectal tumor, intravasation into the lymphatic or vascular systems, survival in circulation, avoidance of host defense mechanisms, arrest at a new site, extravasation into the tissue, and growth at the new site [72]. Among the genes involved are SDF-1α (stromal derived factor-1 alpha) located on chromosome 10 [73], MMP and TIMP (matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases), especially MMP-7 located on chromosome 11, MMP-9 located on chromosome 16, and TIMP-2 located on chromosome 17 [7476], RAD18 located on chromosome 3 [77], and MACC1 (metastasis associated in colorectal cancer 1) located on chromosome 7 [78]. With research, so far, we were able to determine many processes, but the exact molecular pathways need further elucidation. SNPs present a field of ongoing research regarding the incidence and clinical manifestation of CRC and their role as a prognostic and also a predictive factor.

The SDF-1α/CXCR4 axis was initially found to be stimulated by the homing of lymphocytes to inflammatory tissues and has been found to be involved in many areas of immunology and human development, including organogenesis, vascularization, hematopoiesis, and embryogenesis [79]. The SDF-1α/CXCR4 axis promotes metastasis in numerous cancers. SDF-1α is produced and released from tissues such as liver or lung and triggers the migration of tumor cells expressing the CXCR4 receptor thereby promoting invasion, proliferation, and survival under suboptimal condition [80]. Microenvironment conditions such as hypoxia induce CXCR4 expression which further sensitizes tumor cells to signals such as CXCL12 and promotes tumor metastasis. All these factors show a strong correlation between SDF-1α/CXCR4 gene expression and worse prognosis [81]. SNPs of the SDF-1α gene have also been studied as a factor of an increased likelihood of developing cancer. SDF-1α G801A polymorphism in the untranslated 3′ region was associated with increased likelihood of developing breast and lung cancer [82, 83]. It also increases the likelihood of dissemination of breast cancer and leukemia [84, 85]. Chang et al. [86] conducted a clinical trial regarding the frequency of six SNPs of the SDF-1α gene in patients with T3 colon cancer with and without lymph node metastasis. Among the six SNPs, the frequency of GA/AA genotype of G801A (G12197A, rs1801157) was significantly higher in patients with lymph node metastasis than in those without metastasis. In addition, an investigation of the relationship between SDF-1α genotypes and different clinicopathological prognostic factors revealed a positive association between the GA/AA genotype and lymphovascular invasion. Systemic dissemination and the frequency of SDF-1α polymorphisms were not evaluated. Based on these results, a novel therapeutic strategy might be inhibition of the activated SDF-1α/CXCR4 signal pathway.

MACC1 is a regulator of the HGF/Met signaling pathway and plays a key role in regulating many biological processes including cellular proliferation, cell metastasis, cell invasiveness, and angiogenesis. Furthermore, the activation of the HGF/Met signaling pathway was also a key step to epithelial-mesenchymal transition, inducing increased invasiveness, tumorigenesis, and also chemoresistance [87]. The MACC1 gene was discovered by a genome-wide search in human colon cancer tissues, metastases, and normal tissues. High expression levels of MACC1 correlate positively with colon cancer metastases and reduced metastasis-free survival [78]. It has been shown that overexpression of MACC1 correlates better with unfavorable pathologic features than overexpression of MET [88]. Studies indicate that MACC1 may also involve other signaling pathways such as AKT and Ras/ERK. It may also affect levels of MMP-2 and MMP-9 [89]. MACC1 promotes the carcinogenesis of CRC and is associated with the transition from adenoma to carcinoma and the invasive growth of early CRC [90]. MACC1, HGF, and MET are all located on chromosome 7 and amongst their neighbors are genes that are known to be involved in signal transduction and regulation of cell adhesion and motility. For instance, TWIST as well as ITGB8 is known to contribute to the tumorigenesis and metastasis of CRC [91]. Expression levels of MACC1 in colon cancer without distant metastases were significantly higher in primary tumors that later developed distant metastases, compared to those that did not metastasize within a 10-year follow-up period. Thus, MACC1 represents an early prognostic indicator for colon cancer metastases that is independent of age, sex, tumor infiltration, nodal status, and lymph vessel invasion [92]. Several SNPs have been discovered in the human MACC1 gene and Lang et al. conducted a trial researching six SNPs in MACC1 gene from formalin-fixed paraffin-embedded CRC tissue. They reported a positive association of the MACC1 tagging SNP rs1990172 located in the intron region of a gene with reduced overall survival in patients with CRC. Remaining SNPs of the MACC1 locus did not show a significant impact on overall survival [93]. Schmid et al. [94] conducted a trial on SNPs in the coding region of MACC1 and the clinical outcome of CRC and discovered that SNP might be associated with a reduced survival for younger colon cancer patients in early stages.

The genetic polymorphisms of DNA repair genes were analyzed to determine the susceptibility to several cancers including lung, head and neck, breast, bladder, leukemia, and also colorectal cancer. The RAD18 gene combines two distinct pathways maintaining genome stability. On the one hand, RAD18 acts with E2 conjugating enzyme RAD6 to promote PCNA monoubiquitination at stalled replication forks, which initiate the DNA damage bypass pathway. On the other hand, RAD18 can also transmit DNA damage signaling to elicit homologous recombination repair after DNA damage, via a well-defined DNA damage signaling pathway [95]. DNA lesions induced by mutagens, including UV light and chemicals, are thereby efficiently removed. RAD18 recruits RAD6 to the site of DNA damage and the complex binds to damaged DNA by the single-stranded via DNA-binding activity of RAD18, where RAD6 then modulates stalled DNA replication through their ubiquitin-conjugating activity [96]. Kanzaki et al. [77] conducted a study in Japan regarding correlation of SNPs in the RAD18 gene and risk of CRC and they discovered that SNP Arg302Gln is associated with increased risk of CRC. They also found a significant association between polymorphism and clinicopathological features, specifically in differentiated grade and lymph node metastasis. Pan et al. [97] conducted a study in China regarding SNPs in TLS (translesion synthesis polymerases) and susceptibility and metastasis in CRC. They discovered that SNPs in two TLS genes increased the risk of developing CRC and that polymorphism rs373572 in RAD18 is significantly related to an increased risk of metastasis in CRC patients.

MMPs form a family of zinc dependent endopeptidases that degrade the extracellular matrix, but also nonmatrix, proteins. There are 24 known human MMPs, and they are classified based partly on their substrate specificity and partly on their cellular localization as follows: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMP, and others [98]. Function of MMPs is regulated by another group of enzymes named TIMP. This group encompasses four TIMPs: TIMP-1, TIMP-2, TIMP-3, and TIMP-4 [99]. The MMPs and TIMPs play a key role in the normal physiology of connective tissue during development, morphogenesis, and wound healing, but their unregulated activity has been implicated in numerous disease processes including arthritis, atherosclerosis, and tumor cell metastasis [100]. It has been proposed that MMPs and TIMPs might play a role not only in tumor invasion and initiation of metastasis, but also in carcinogenesis from colorectal adenomas, and several studies demonstrated that high preoperative serum or plasma MMPs and TIMPs antigen levels are strong predictive factors for poor prognosis in patients with CRC [101]. The overexpression of MMP-7, MMP-9, and TIMP-2 indicates they have considerable metastatic potential and correlates with unfavorable clinicopathological characteristics [102, 103]. Further studies discovered the impact of SNPs in genes MMP-7, MMP-9, and TIMP-2 in CRC tumor progression and metastasis. Park et al. [104] conducted a study in Korea regarding the impact of SNPs in genes TIMP-2, MMP-2, and MMP-9 on clinical characteristics in CRC. The study demonstrated that SNPs in TIMP-2 are associated with CRC susceptibility and pathological characteristics. Of special interest is the fact that the frequency of TIMP-2 rs81799090 genotype G/G was higher in patients with metastasis than in those without metastasis. Dziki et al. [105] conducted a study in Poland regarding rs11568818 polymorphism of the MMP-7 gene promoter region in CRC. They discovered a possible relationship between functional SNP and the susceptibility to development of CRC and an aggressive course of the disease. Xing et al. [106] conducted a study to explore the role of the MMP-9 polymorphism in CRC. Their results indicate that the MMP-9 1562C>T rs3918242 polymorphism located within an important regulatory element that appears to be a binding site for a transcription repressor protein affects lymph node metastasis in CRC.

6. Conclusion

The search for new prognostic factors, either new biomarkers or modified pathohistological characteristics, is a never-ending story and it will be the subject of further research. A personalized approach in medicine has in the last decade changed the field of oncology. The clinical and pathological TNM staging system is still the most important prognostic factor, but in certain cancers and stages due to heterogeneous disease, it produces limited prognostic and no predictive information.

Novel molecular targets and therapeutic agents have led to the study of biomarkers as prognostic and predictive factors. Understanding the molecular mechanisms underlying the carcinogenesis and metastatic process will help us to identify those at the highest risk of recurrence and to find new tumor targets to prevent disease progression. One of the novel biomarkers in CRC might be SNPs that influence disease incidence and have the potential of becoming a prognostic and/or predictive factor for everyday clinical practice and decision making; however, it is important to identify those SNPs with the strongest predisposition.

Surgery is still the mainstay of CRC treatment, but chemotherapy further lowers recurrence rate and improves survival. It is important to treat patients with resectable CRC as effectively as possible, choosing patients with the highest probability of recurrence that benefit the most from adjuvant treatment and not to overtreat patients with low probability of disease recurrence. More intensive follow-up strategies might also be applied in patients with higher recurrence probability. Furthermore, targeted strategies against these aforementioned genes might prove to be a reasonable therapeutic option.

The potential characteristics of SNPs have special significance in that they may enable us to discover patients with higher risks of disease recurrence of stage I and stage II. In addition, the potential effect of SNPs on chemotherapy metabolism may also be of great benefit. Individualized decision making is recommended given the unclear benefit of adjuvant chemotherapy in unselected patients of stages I and II. Therefore, it would be useful to determine SNPs of genes involved in the metastatic process of CRC and chemotherapy metabolism and to test their clinical significance.

Due to effectiveness, side effects, and costs, there is further need for patient-tailored therapy in the adjuvant setting, as we have in the metastatic setting with KRAS testing and choice of appropriate targeted therapy. Studies are being conducted on biomarkers such as SNPs from tumor tissue, lymph nodes, and peripheral blood, in order to determine molecular factors for patient and selection. Promising results have been discovered, but most of them need further validation in larger prospective clinical trials.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. International Agency for Research on Cancer, World Cancer Report 2014, International Agency for Research on Cancer, World Health Organization, 2014.
  2. L. A. G. Ries, D. Melbert, M. Krapcho et al., SEER Cancer Statistics Review 1975–2005, National Cancer Institute, Rockville, Md, USA, 2007.
  3. S. Edge, D. Byrd, C. Compton et al., AJCC Cancer Staging Manual, Springer, New York, NY, USA, 7th edition, 2009.
  4. R. K. Kelley and A. P. Venook, “Prognostic and predictive markers in stage II colon cancer: is there a role for gene expression profiling?” Clinical Colorectal Cancer, vol. 10, no. 2, pp. 73–80, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. A. B. Benson III, D. Schrag, M. R. Somerfield et al., “American society of clinical oncology recommendations on adjuvant chemotherapy for stage II colon cancer,” Journal of Clinical Oncology, vol. 22, no. 16, pp. 3408–3419, 2004. View at Publisher · View at Google Scholar · View at Scopus
  6. P. F. Engstrom, P. J. Arnoletti, A. B. Benson et al., “NCCN clinical practice guidelines in oncology: colon cancer,” National Comprehensive Cancer Network, vol. 7, pp. 778–831, 2009. View at Google Scholar
  7. R. Labianca, B. Nordlinger, G. D. Beretta, A. Brouquet, and A. Cervantes, “Primary colon cancer: ESMO clinical practice guidelines for diagnosis, adjuvant treatment and follow-up,” Annals of Oncology, vol. 21, supplement 5, pp. v70–v77, 2010. View at Publisher · View at Google Scholar · View at Scopus
  8. H. J. Freeman, “Early stage colon cancer,” World Journal of Gastroenterology, vol. 19, no. 46, pp. 8468–8473, 2013. View at Publisher · View at Google Scholar · View at Scopus
  9. T. Akiyoshi, T. Kobunai, and T. Watanabe, “Recent approaches to identifying biomarkers for high-risk stage II colon cancer,” Surgery Today, vol. 42, no. 11, pp. 1037–1045, 2012. View at Publisher · View at Google Scholar · View at Scopus
  10. D. G. Nicastri, J. T. Doucette, T. E. Godfrey, and S. J. Hughes, “Is occult lymph node disease in colorectal cancer patients clinically significant? A review of the relevant literature,” Journal of Molecular Diagnostics, vol. 9, no. 5, pp. 563–571, 2007. View at Publisher · View at Google Scholar · View at Scopus
  11. S. C. Bruin, Y. He, I. Mikolajewska-Hanclich et al., “Molecular alterations associated with liver metastases development in colorectal cancer patients,” British Journal of Cancer, vol. 105, no. 2, pp. 281–287, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. A. Bolocan, D. Ion, D. N. Ciocan, and D. N. Paduraru, “Prognostic and predictive factors in colorectal cancer,” Chirurgia, vol. 107, no. 5, pp. 555–563, 2012. View at Google Scholar · View at Scopus
  13. H. C. van Wyk, J. Park, C. Roxburgh, P. Horgan, A. Foulis, and D. C. McMillan, “The role of tumour budding in predicting survival in patients with primary operable colorectal cancer: a systematic review,” Cancer Treatment Reviews, vol. 41, no. 2, pp. 151–159, 2015. View at Publisher · View at Google Scholar · View at Scopus
  14. S. Pernot, M. Terme, T. Voron et al., “Colorectal cancer and immunity: what we know and perspectives,” World Journal of Gastroenterology, vol. 20, no. 14, pp. 3738–3750, 2014. View at Publisher · View at Google Scholar · View at Scopus
  15. H. Ueno, Y. Kajiwara, H. Shimazaki et al., “New criteria for histologic grading of colorectal cancer,” The American Journal of Surgical Pathology, vol. 36, no. 2, pp. 193–201, 2012. View at Publisher · View at Google Scholar · View at Scopus
  16. I. D. Nagtegaal, C. A. M. Marijnen, E. K. Kranenbarg, C. J. H. Van De Velde, and J. H. J. M. Van Krieken, “Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: not one millimeter but two millimeters is the limit,” American Journal of Surgical Pathology, vol. 26, no. 3, pp. 350–357, 2002. View at Publisher · View at Google Scholar · View at Scopus
  17. S. C. Glasgow, J. I. S. Bleier, L. J. Burgart, C. O. Finne, and A. C. Lowry, “Meta-analysis of histopathological features of primary colorectal cancers that predict lymph node metastases,” Journal of Gastrointestinal Surgery, vol. 16, no. 5, pp. 1019–1028, 2012. View at Publisher · View at Google Scholar · View at Scopus
  18. I. Zlobec and A. Lugli, “Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: tumor budding as oncotarget,” Oncotarget, vol. 1, no. 7, pp. 651–661, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. J. Galon, F. Pagès, F. M. Marincola et al., “Cancer classification using the immunoscore: a worldwide task force,” Journal of Translational Medicine, vol. 10, article 205, 2012. View at Publisher · View at Google Scholar
  20. C. Ratto, L. Sofo, M. Ippoliti et al., “Accurate lymph-node detection in colorectal cancer specimens resected for cancer is of prognostic significance,” Diseases of the Colon & Rectum, vol. 42, pp. 143–154, 1999. View at Google Scholar
  21. A. Mejia, S. Schulz, T. Hyslop, D. S. Weinberg, and S. A. Waldman, “Molecular staging individualizing cancer management,” Journal of Surgical Oncology, vol. 105, no. 5, pp. 468–474, 2012. View at Publisher · View at Google Scholar · View at Scopus
  22. D. G. Haller, P. J. Catalano, J. S. Macdonald et al., “Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of intergroup 0089,” Journal of Clinical Oncology, vol. 23, no. 34, pp. 8671–8678, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. C. Twelves, A. Wong, M. P. Nowacki et al., “Capecitabine as adjuvant treatment for stage III colon cancer,” The New England Journal of Medicine, vol. 352, no. 26, pp. 2696–2704, 2005. View at Publisher · View at Google Scholar · View at Scopus
  24. T. André, C. Boni, L. Mounedji-Boudiaf et al., “Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer,” The New England Journal of Medicine, vol. 350, no. 23, pp. 2343–2351, 2004. View at Publisher · View at Google Scholar · View at Scopus
  25. J. P. Kuebler, H. S. Wieand, M. J. O'Connell et al., “Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07,” Journal of Clinical Oncology, vol. 25, no. 16, pp. 2198–2204, 2007. View at Publisher · View at Google Scholar · View at Scopus
  26. D. G. Haller, J. Tabernero, J. Maroun et al., “Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer,” Journal of Clinical Oncology, vol. 29, no. 11, pp. 1465–1471, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. W.-Q. Jiang, F.-F. Fu, Y.-X. Li et al., “Molecular biomarkers of colorectal cancer: prognostic and predictive tools for clinical practice,” Journal of Zhejiang University SCIENCE B, vol. 13, no. 9, pp. 663–675, 2012. View at Publisher · View at Google Scholar
  28. B. Chibaudel, C. Tournigand, T. André, A. K. Larsen, and A. De Gramont, “Targeted therapies as adjuvant treatment for early-stage colorectal cancer: first impressions and clinical questions,” Clinical Colorectal Cancer, vol. 9, no. 5, pp. 269–273, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. QUASAR Collaborative Group, “Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study,” The Lancet, vol. 370, no. 9604, pp. 2020–2029, 2007. View at Publisher · View at Google Scholar · View at Scopus
  30. E. Mamounas, S. Wieand, N. Wolmark et al., “Comparative efficiacy of adjuvant chemotherapy in patients with Dukes B versus Dukes C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies,” Journal of Clinical Oncology, vol. 17, no. 5, pp. 1349–1355, 1999. View at Google Scholar
  31. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators, “Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer,” Journal of Clinical Oncology, vol. 17, no. 15, pp. 1356–1363, 1999. View at Google Scholar
  32. X. Wu, J. Zhang, X. He et al., “Postoperative adjuvant chemotherapy for stage II colorectal cancer: a systematic review of 12 randomized controlled trials,” Journal of Gastrointestinal Surgery, vol. 16, no. 3, pp. 646–655, 2012. View at Publisher · View at Google Scholar · View at Scopus
  33. G. Yothers, M. J. O'Connell, C. J. Allegra et al., “Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses,” Journal of Clinical Oncology, vol. 29, no. 28, pp. 3768–3774, 2011. View at Publisher · View at Google Scholar · View at Scopus
  34. R. Dienstmann, R. Salazar, and J. Tabernero, “Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients,” Journal of Clinical Oncology, vol. 33, no. 16, pp. 1787–1796, 2015. View at Publisher · View at Google Scholar
  35. J. B. O'Connell, M. A. Maggard, and C. Y. Ko, “Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging,” Journal of the National Cancer Institute, vol. 96, no. 19, pp. 1420–1425, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. K. T. Huynh and D. S. B. Hoon, “Epigenetics of regional lymph node metastasis in solid tumors,” Clinical and Experimental Metastasis, vol. 29, no. 7, pp. 747–756, 2012. View at Publisher · View at Google Scholar · View at Scopus
  37. R. Kanthan, J.-L. Senger, and S. C. Kanthan, “Molecular events in primary and metastatic colorectal carcinoma: a review,” Pathology Research International, vol. 2012, Article ID 597497, 14 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  38. R. M. Goldberg, I. Tabah-Fisch, H. Bleiberg et al., “Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer,” Journal of Clinical Oncology, vol. 24, no. 25, pp. 4085–4091, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. P. A. Jones and S. B. Baylin, “The epigenomics of cancer,” Cell, vol. 128, no. 4, pp. 683–692, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. M. Dean, T. Fojo, and S. Bates, “Tumour stem cells and drug resistance,” Nature Reviews Cancer, vol. 5, no. 4, pp. 275–284, 2005. View at Publisher · View at Google Scholar · View at Scopus
  41. F. T. Bosman and P. Yan, “Molecular pathology of colorectal cancer,” Polish Journal of Pathology, vol. 65, no. 4, pp. 257–266, 2014. View at Publisher · View at Google Scholar · View at Scopus
  42. S. Popat, R. Hubner, and R. S. Houlston, “Systematic review of microsatellite instability and colorectal cancer prognosis,” Journal of Clinical Oncology, vol. 23, no. 3, pp. 609–618, 2005. View at Publisher · View at Google Scholar · View at Scopus
  43. G. des Guetz, O. Schischmanoff, P. Nicolas, G.-Y. Perret, J.-F. Morere, and B. Uzzan, “Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis,” European Journal of Cancer, vol. 45, no. 10, pp. 1890–1896, 2009. View at Publisher · View at Google Scholar · View at Scopus
  44. Z. Saridaki, J. Souglakos, and V. Georgoulias, “Prognostic and predictive significance of MSI in stages II/III colon cancer,” World Journal of Gastroenterology, vol. 20, no. 22, pp. 6809–6814, 2014. View at Publisher · View at Google Scholar · View at Scopus
  45. G. Lech, R. Slotwinski, and I. W. Krasnodebski, “The role of tumour markers and biomarkers in colorectal cancer,” Neoplasma, vol. 61, no. 1, pp. 1–8, 2014. View at Publisher · View at Google Scholar · View at Scopus
  46. M. M. Bertagnolli, D. Niedzwiecki, C. C. Compton et al., “Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer. Cancer and Leukemia Group B Protocol 89803,” Journal of Clinical Oncology, vol. 27, no. 11, pp. 1814–1821, 2009. View at Publisher · View at Google Scholar
  47. A. de la Chapelle, “Genetic predisposition to colorectal cancer,” Nature Reviews Cancer, vol. 4, no. 10, pp. 769–780, 2004. View at Publisher · View at Google Scholar · View at Scopus
  48. A. de la Chapelle, “The incidence of Lynch syndrome,” Familial Cancer, vol. 4, no. 3, pp. 233–237, 2005. View at Publisher · View at Google Scholar · View at Scopus
  49. I. N. Mates, V. Jinga, I. E. Csiki et al., “Single nucleotide polymorphisms in colorectal cancer: associations with tumor site and TNM stage,” Journal of Gastrointestinal and Liver Diseases, vol. 21, no. 1, pp. 45–52, 2012. View at Google Scholar · View at Scopus
  50. P. Lichtenstein, N. V. Holm, P. K. Verkasalo et al., “Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland,” The New England Journal of Medicine, vol. 343, no. 2, pp. 78–85, 2000. View at Publisher · View at Google Scholar · View at Scopus
  51. M. W. Nachman, “Single nucleotide polymorphisms and recombination rate in humans,” Trends in Genetics, vol. 17, no. 9, pp. 481–485, 2001. View at Publisher · View at Google Scholar · View at Scopus
  52. K. Mimori, F. Tanaka, K. Shibata, and M. Mori, “Review: single nucleotide polymorphisms associated with the oncogenesis of colorectal cancer,” Surgery Today, vol. 42, no. 3, pp. 215–219, 2012. View at Publisher · View at Google Scholar · View at Scopus
  53. M. A. Varela and W. Amos, “Heterogeneous distribution of SNPs in the human genome: microsatellites as predictors of nucleotide diversity and divergence,” Genomics, vol. 95, no. 3, pp. 151–159, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. T. A. Manolio, “Genomewide association studies and assessment of the risk of disease,” The New England Journal of Medicine, vol. 363, no. 2, pp. 166–176, 2010. View at Publisher · View at Google Scholar
  55. M. Aiello, N. Vella, C. Cannavò et al., “Role of genetic polymorphisms and mutations in colorectal cancer therapy,” Molecular Medicine Reports, vol. 4, no. 2, pp. 203–208, 2011. View at Publisher · View at Google Scholar · View at Scopus
  56. A. de Gramont, A. Figer, M. Seymour et al., “Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer,” Journal of Clinical Oncology, vol. 18, no. 16, pp. 2938–2947, 2000. View at Google Scholar · View at Scopus
  57. Y. Dong, J. W. Liu, Y. J. Gao, T. Zhou, and Y. M. Chen, “Relationship between DNA repair gene XPD751 single-nucleotide polymorphisms and prognosis of colorectal cancer,” Genetics and Molecular Research, vol. 14, no. 2, pp. 5390–5398, 2015. View at Publisher · View at Google Scholar
  58. J. Stoehlmacher, V. Ghaderi, S. Iqbal et al., “A polymorphism of the XRCC1 gene predicts for response to platinum based treatment in advanced colorectal cancer,” Anticancer Research, vol. 21, no. 4, pp. 3075–3079, 2001. View at Google Scholar · View at Scopus
  59. F. Ye, Z. Liu, A. Tan, M. Liao, Z. Mo, and X. Yang, “XRCC1 and GSTP1 polymorphisms and prognosis of oxaliplatin-based chemotherapy in colorectal cancer: a meta-analysis,” Cancer Chemotherapy and Pharmacology, vol. 71, no. 3, pp. 733–740, 2013. View at Publisher · View at Google Scholar · View at Scopus
  60. J. Stoehlmacher, D. J. Park, W. Zhang et al., “Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer,” Journal of the National Cancer Institute, vol. 94, no. 12, pp. 936–942, 2002. View at Publisher · View at Google Scholar · View at Scopus
  61. J. H. Park, N. S. Kim, J. Y. Park et al., “MGMT −535G>T polymorphism is associated with prognosis for patients with metastatic colorectal cancer treated with oxaliplatin-based chemotherapy,” Journal of Cancer Research and Clinical Oncology, vol. 136, no. 8, pp. 1135–1142, 2010. View at Publisher · View at Google Scholar
  62. M.-C. Etienne-Grimaldi, G. Milano, F. Maindrault-Gœbel et al., “Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients,” British Journal of Clinical Pharmacology, vol. 69, no. 1, pp. 58–66, 2010. View at Publisher · View at Google Scholar · View at Scopus
  63. O. Castillo-Fernandeza, M. Santibanezb, A. Bauzab et al., “Methylenetetetrahydrofolate reductase polymorphism (677C>T) predicts long time to progression in metastatic colorectal cancer treated with 5-fluorouracil and folinic acid,” Archives of Medical Research, vol. 41, pp. 430–435, 2010. View at Google Scholar
  64. E. Cecchin, G. Perrone, S. Nobili et al., “MTHFR-1298 A>C (rs1801131) is a predictor of survival in two cohorts of stage II/III colorectal cancer patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin,” The Pharmacogenomics Journal, vol. 15, pp. 219–225, 2015. View at Publisher · View at Google Scholar · View at Scopus
  65. E. J. Kap, S. Richter, A. Rudolph et al., “Genetic variants in the glutathione S-transferase genes and survival in colorectal cancer patients after chemotherapy and differences according to treatment with oxaliplatin,” Pharmacogenetics and Genomics, vol. 24, no. 7, pp. 340–347, 2014. View at Publisher · View at Google Scholar · View at Scopus
  66. G. Absenger, L. Benhaim, J. Szkandera et al., “The cyclin D1 (CCND1) rs9344 G>A polymorphism predicts clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy,” Pharmacogenomics Journal, vol. 14, no. 2, pp. 130–134, 2014. View at Publisher · View at Google Scholar · View at Scopus
  67. D. Páez, A. Gerger, W. Zhang et al., “Association of common gene variants in the WNT/β-catenin pathway with colon cancer recurrence,” Pharmacogenomics Journal, vol. 14, no. 2, pp. 142–150, 2014. View at Publisher · View at Google Scholar · View at Scopus
  68. D. Caronia, M. Martin, J. Sastre et al., “A polymorphism in the cytidine deaminase promoter predicts severe capecitabine-induced hand-foot syndrome,” Clinical Cancer Research, vol. 17, no. 7, pp. 2006–2013, 2011. View at Publisher · View at Google Scholar · View at Scopus
  69. M. Gusella, A. C. Frigo, C. Bolzonella et al., “Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer,” British Journal of Cancer, vol. 100, no. 10, pp. 1549–1557, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. A. A. Argyriou, G. Cavaletti, A. Antonacopoulou et al., “Voltage-gated sodium channel polymorphisms play a pivotal role in the development of oxaliplatin-induced peripheral neurotoxicity: results from a prospective multicenter study,” Cancer, vol. 119, no. 19, pp. 3570–3577, 2013. View at Publisher · View at Google Scholar · View at Scopus
  71. A. Custodio, J. Moreno-Rubio, J. Aparicio et al., “Pharmacogenetic predictors of severe peripheral neuropathy in colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy: a GEMCAD group study,” Annals of Oncology, vol. 25, no. 2, Article ID mdt546, pp. 398–403, 2014. View at Publisher · View at Google Scholar · View at Scopus
  72. K. Jin, W. Gao, Y. Lu, H. Lan, L. Teng, and F. Cao, “Mechanisms regulating colorectal cancer cell metastasis into liver (review),” Oncology Letters, vol. 3, no. 1, pp. 11–15, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. O. Kollmar, K. Rupertus, C. Scheuery et al., “Stromal cell-derived factor-1 promotes cell migration and tumor growth of colorectal metastasis,” Neoplasia, vol. 9, no. 10, pp. 862–870, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. B. Gentner, A. Wein, R. S. Croner et al., “Differences in the gene expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in primary colorectal tumors and their synchronous liver metastases,” Anticancer Research, vol. 29, no. 1, pp. 67–74, 2009. View at Google Scholar · View at Scopus
  75. M. Illemann, N. Bird, A. Majeed et al., “MMP-9 is differentially expressed in primary human colorectal adenocarcinomas and their metastases,” Molecular Cancer Research, vol. 4, no. 5, pp. 293–302, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. S. Koskensalo, J. Louhimo, S. Nordling, J. Hagström, and C. Haglund, “MMP-7 as a prognostic marker in colorectal cancer,” Tumor Biology, vol. 32, no. 2, pp. 259–264, 2011. View at Publisher · View at Google Scholar · View at Scopus
  77. H. Kanzaki, M. Ouchida, H. Hanafusa et al., “Single nucleotide polymorphism in the RAD18 gene and risk of colorectal cancer in the Japanese population,” Oncology Reports, vol. 18, no. 5, pp. 1171–1175, 2007. View at Google Scholar · View at Scopus
  78. U. Stein, W. Walther, F. Arlt et al., “MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis,” Nature Medicine, vol. 15, no. 1, pp. 59–67, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. N. Yoshitake, H. Fukui, H. Yamagishi et al., “Expression of SDF-1α and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer,” British Journal of Cancer, vol. 98, no. 10, pp. 1682–1689, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. R. Matsusue, H. Kubo, S. Hisamori et al., “Hepatic stellate cells promote liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis,” Annals of Surgical Oncology, vol. 16, no. 9, pp. 2645–2653, 2009. View at Publisher · View at Google Scholar · View at Scopus
  81. I. Kryczek, S. Wei, E. Keller, R. Liu, and W. Zou, “Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis,” The American Journal of Physiology—Cell Physiology, vol. 292, no. 3, pp. C987–C995, 2007. View at Publisher · View at Google Scholar · View at Scopus
  82. A. Zafiropoulos, N. Crikas, A. M. Passam, and D. A. Spandidos, “Significant involvement of CCR2-64I and CXCL12-3a in the development of sporadic breast cancer,” Journal of Medical Genetics, vol. 41, article e59, 2004. View at Publisher · View at Google Scholar · View at Scopus
  83. A. Coelho, C. Calçada, R. Catarino, D. Pinto, G. Fonseca, and R. Medeiros, “CXCL12-3′ A polymorphism and lung cancer metastases protection: new perspectives in immunotherapy?” Cancer Immunology, Immunotherapy, vol. 55, no. 6, pp. 639–643, 2006. View at Publisher · View at Google Scholar · View at Scopus
  84. F. Dommange, G. Cartron, C. Espanel et al., “CXCL12 polymorphism and malignant cell dissemination/tissue infiltration in acute myeloid leukemia,” The FASEB Journal, vol. 20, no. 11, pp. 1913–1915, 2006. View at Publisher · View at Google Scholar · View at Scopus
  85. S. Hassan, A. Baccarelli, O. Salvucci, and M. Basik, “Plasma stromal cell-derived factor-1: host derived marker predictive of distant metastasis in breast cancer,” Clinical Cancer Research, vol. 14, no. 2, pp. 446–454, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. S.-C. Chang, P.-C. Lin, S.-H. Yang, H.-S. Wang, A. F.-Y. Li, and J.-K. Lin, “SDF-1alpha G801A polymorphism predicts lymph node metastasis in stage T3 colorectal cancer,” Annals of Surgical Oncology, vol. 16, no. 8, pp. 2323–2330, 2009. View at Publisher · View at Google Scholar · View at Scopus
  87. I. Cañadas, Á. Taus, I. González et al., “High circulating hepatocyte growth factor levels associate with epithelial to mesenchymal transition and poor outcome in small cell lung cancer patients,” Oncotarget, vol. 5, no. 14, pp. 5246–5256, 2014. View at Publisher · View at Google Scholar · View at Scopus
  88. D. Ji, Z.-T. Lu, Y.-Q. Li et al., “MACC1 expression correlates with PFKFB2 and survival in hepatocellular carcinoma,” Asian Pacific Journal of Cancer Prevention, vol. 15, no. 2, pp. 999–1003, 2014. View at Publisher · View at Google Scholar · View at Scopus
  89. K. Zhang, F. Tian, Y. Zhang et al., “MACC1 is involved in the regulation of proliferation, colony formation, invasion ability, cell cycle distribution, apoptosis and tumorigenicity by altering Akt signaling pathway in human osteosarcoma,” Tumor Biology, vol. 35, no. 3, pp. 2537–2548, 2014. View at Publisher · View at Google Scholar · View at Scopus
  90. B. Ren, V. Zakharov, Q. Yang, L. McMahon, J. Yu, and W. Cao, “MACC1 is related to colorectal cancer initiation and early-stage invasive growth,” American Journal of Clinical Pathology, vol. 140, no. 5, pp. 701–707, 2013. View at Publisher · View at Google Scholar · View at Scopus
  91. U. Stein, M. Dahlmann, and W. Walther, “MACC1-more than metastasis? Facts and predictions about a novel gene,” Journal of Molecular Medicine, vol. 88, no. 1, pp. 11–18, 2010. View at Publisher · View at Google Scholar · View at Scopus
  92. F. Arlt and U. Stein, “Colon cancer metastasis: MACC1 and Met as metastatic pacemakers,” The International Journal of Biochemistry and Cell Biology, vol. 41, no. 12, pp. 2356–2359, 2009. View at Publisher · View at Google Scholar · View at Scopus
  93. A. H. Lang, S. Geller-Rhomberg, T. Winder et al., “A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients,” BMC Cancer, vol. 12, article 20, 2012. View at Publisher · View at Google Scholar · View at Scopus
  94. F. Schmid, S. Burock, K. Klockmeier, P. M. Schlag, and U. Stein, “SNPs in the coding region of the metastasis-inducing gene MACC1 and clinical outcome in colorectal cancer,” Molecular Cancer, vol. 11, article 49, 2012. View at Publisher · View at Google Scholar · View at Scopus
  95. L. Ting, H. Jun, and C. Junjie, “RAD18 lives a double life: its implication in DNA double-strand break repair,” DNA Repair, vol. 9, no. 12, pp. 1241–1248, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. S. Tateishi, Y. Sakuraba, S. Masuyama, H. Inoue, and M. Yamaizumi, “Dysfunction of human Rad18 results in defective postreplication repair and hypersensitivity to multiple mutagens,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 14, pp. 7927–7932, 2000. View at Publisher · View at Google Scholar · View at Scopus
  97. J. Pan, P. Chi, X. Lu, and Z. Xu, “Genetic polymorphisms in translesion synthesis genes are associated with colorectal cancer risk and metastasis in Han Chinese,” Gene, vol. 504, no. 2, pp. 151–155, 2012. View at Publisher · View at Google Scholar · View at Scopus
  98. K. A. Paschos, D. Canovas, and N. C. Bird, “Enzymatic function of multiple origins regulates the progression of colorectal cancer and the development of metastases,” Hippokratia, vol. 13, no. 1, pp. 23–31, 2009. View at Google Scholar · View at Scopus
  99. C. Amalinei, I. D. Caruntu, S. E. Giusca, and R. A. Bălan, “Matrix metalloproteinases involvement in pathologic conditions,” Romanian Journal of Morphology and Embryology, vol. 51, no. 2, pp. 215–228, 2010. View at Google Scholar
  100. K. Brew, D. Dinakarpandian, and H. Nagase, “Tissue inhibitors of metalloproteinases: evolution, structure and function,” Biochimica et Biophysica Acta—Protein Structure and Molecular Enzymology, vol. 1477, no. 1-2, pp. 267–283, 2000. View at Publisher · View at Google Scholar · View at Scopus
  101. L. Herszényi, I. Hritz, G. Lakatos, M. Z. Varga, and Z. Tulassay, “The Behavior of matrix metalloproteinases and their inhibitors in colorectal cancer,” International Journal of Molecular Sciences, vol. 13, no. 10, pp. 13240–13263, 2012. View at Publisher · View at Google Scholar · View at Scopus
  102. V. Şurlin, M. Ioana, and I. E. Pleşea, “Genetic patterns of metalloproteinases and their tissular inhibitors-clinicopathologic and prognostic significance in colorectal cancer,” Romanian Journal of Morphology and Embryology, vol. 52, no. 1, pp. 231–236, 2011. View at Google Scholar · View at Scopus
  103. A. V. Chernov, N. E. Sounni, A. G. Remacle, and A. Y. Strongin, “Epigenetic control of the invasion-promoting MT1-MMP/MMP-2/TIMP-2 axis in cancer cells,” Journal of Biological Chemistry, vol. 284, no. 19, pp. 12727–12734, 2009. View at Publisher · View at Google Scholar · View at Scopus
  104. K. S. Park, S. J. Kim, K. H. Kim, and J. C. Kim, “Clinical characteristics of TIMP2, MMP2, and MMP9 gene polymorphisms in colorectal cancer,” Journal of Gastroenterology and Hepatology, vol. 26, no. 2, pp. 391–397, 2011. View at Publisher · View at Google Scholar · View at Scopus
  105. Ł. Dziki, K. Przybyłowska, I. Majsterek, R. Trzciński, and M. Sygut, “A/G Polymorphism of the MMP-7 gene promoter region in colorectal cancer,” Polski Przeglad Chirurgiczny, vol. 83, no. 11, pp. 622–626, 2011. View at Publisher · View at Google Scholar · View at Scopus
  106. L.-L. Xing, Z.-N. Wang, L. Jiang et al., “Matrix metalloproteinase-9-1562C>T polymorphism may increase the risk of lymphatic metastasis of colorectal cancer,” World Journal of Gastroenterology, vol. 13, no. 34, pp. 4626–4629, 2007. View at Publisher · View at Google Scholar · View at Scopus