Genetic and Chromosomal Aberrations and Their Clinical Significance in Renal Neoplasms

Table 1

(a) Chromosome and genetic aberrations in clear cell RCC. (b) Chromosome and genetic aberrations in papillary RCC. (c) Chromosome and genetic aberrations in chRCC, RO, and CDRCC.

(a)

Chromosome	Type of genetic alteration	Candidate gene	Incidence	Function of protein	Prognosis
3p25-26	LOH, hypermethylation, mutations	VHL	Found in 57–91% of tumours [30, 31, 37, 40, 163–165]	pVHL targets HIFa degradation; nonfunctioning pVHL does not degrade HIFa leading to angiogenesis	No clear association between VHL status and tumour grade and stage or survival of patients [31, 36–38, 40, 165]
3p14.2	LOH, translocation, hypermethylation	FHIT; contains chromosome fragile site FRA3B	Aberrations in 69–90% of ccRCC [62, 64, 78, 166]; 51–90% of ccRCCs showed reduced or absent FHIT protein expression [72, 74, 77]	FHIT protein is involved in apoptosis and proliferation [167–170]	FHIT loss, an early event in RCC; correlation of inactivation with lower grade and stage as well as better survival [73, 74, 77, 78]
3p21.3	Hypermethylation	RASSF1A	Methylation in 23–91% ccRCC tumours [88, 171]	RASSF1A promotes cell cycle arrest, apoptosis, and microtubule stability [79]	Hypermethylation of the RASSF1A promoter is significantly associated with advanced stage, grade, and worse cancer specific survival [85, 86]; loss of RASS1A protein is found in most ccRCC; but tumours with RASSF1A immunopositivity associated with higher stage, grade, and worse survival [87]
3p21	Truncating and missense mutations	PBRM1	Mutations in 29–41% of ccRCC tumours [90, 92, 105, 109]	BAF180 subunit of the SWI/SNF (switch and sucrose nonfermentable) chromatin remodeling complex; SWI/SNF complex regulates cell differentiation, proliferation, replication, transcriptional regulation, and DNA repair [90, 172, 173]	Due to contradictory findings, relationship of PBRM1 status and prognosis is still unclear [103–106]
1p36.11	Copy number loss	ARID1A	Copy number loss in 16% of patients with ccRCC [93]	BAF250a subunit of SWI/SNF complex	Low ARID1A mRNA and BAF250a immunostaining associated with higher stage, grade, and worse disease-free and disease specific survival [93, 111]
3p21.3	Truncating and missense mutations	BAP1	Inactivated in 6–15% of ccRCC [91, 92, 105, 109]	BAP1 is involved in cell cycle regulation [174]	BAP1 is an indicator of worse prognosis [91, 105, 107–110]
3p21.31	Truncating and missense mutations	SETD2	Mutation in 8–16% of tumours [92, 105, 109]	SETD2 is a histone methyltransferase controlling transcriptional regulation [175]	SETD2 mutation associated with worse disease specific survival [105]
Xp11.2	Truncating and missense mutations	KDM5C	Mutation in 4–8% of tumours [92, 109]	Histone demethylase, transcriptional regulation [176]	Tumours with mutations in BAP1, SETD2, or KDM5C are significantly associated with higher stage [92]
5q21.2~q21.3	Copy number loss or gain	NA	Copy number gain in 32–34% and loss in 52–56.2% of tumours [112, 113]	NA	Significant association of loss at 5q21.2~q21.3 with high grade tumours in patients with 3p loss [113]
5q22~q23	Copy number loss or gain	NA	Gains in 48–52.4% and loss in 42.9–46% of tumours [112, 113]	NA	Gain at 5q22.3~q23.2 associated with smaller, low grade tumours and better disease specific survival; loss at 5q22.3~q23.2 significantly related to larger, high grade tumours and poor disease specific survival [112, 113]
5q31–qter	Copy number gain	NA	Gain in of 56.8% ccRCCs [112]	NA	Gain of 5q31–qter had better overall survival compared with patients without gain of 5q [114]
8p	LOH	NA	LOH in 32-33% of RCC tissue specimen [115, 116, 177]	NA	LOH on chromosomes 8p and 9p, a significant predictor of recurrence [115]; LOH of 8p correlated with higher stage and grade [116]
9p	LOH	Possible candidate gene at 9p21; CDK2NA/ARF [118, 119]	LOH in 14–33% of RCC tissue specimen [115, 117, 119]	p16 is the protein product of CDK2NA which regulates cell cycle [118, 119]	Associated with high grade and stage, lymph node involvement, metastases, recurrence, and worse survival [115, 117–120]
14q	LOH	Possible HIF1A at 14q23.2 [121]	Loss in 38–55% of tumours [116, 121, 178, 179]	HIF1a is a transcription factor which regulates cellular response during hypoxia, for example, angiogenesis	Correlation of LOH at 14q with advanced stage, grade, larger tumour size, recurrence, and shorter cancer specific survival [116, 121, 178–180]
Chromosome 7	Polysomy	NA	Polysomy 7 in 9.5–56.2% ccRCC [133, 181]	NA	Polysomy 7 associated with higher tumour grade, stage, and higher proliferative rate [133]

NA indicates not available.

(b)

Chromosome	Type of genetic alteration	Candidate gene	Incidence	Function of protein	Prognosis
Chromosome 7	Polysomy	NA	Polysomy 7 in 50–100% pRCC [133, 181, 182]	NA	Polysomy 7 is not correlated with survival, clinical features, or proliferation rate of pRCC [132, 133, 136, 137]
7q31	Missense mutation, gene duplication	MET	MET mutation present in 5–21.6% of sporadic pRCC [8, 108, 139, 141]; copy number gains in 46% of type II pRCC and in 81% of type I pRCC [108]; strong c-met protein expression in 80–90% of sporadic pRCC [143, 144]	The c-met protein is involved in cell proliferation, motility, differentiation, invasion, and angiogenesis [142, 143]	One study showed association of increasing tumour stage with c-met expression and a trend of better overall survival in patients with no c-met expression in tumours [143]
Chromosome 17	Polysomy	NA	Gains in 14.3–95.5% of pRCC [132, 134, 137, 158, 183]	NA	Trisomy 17 associated with better prognosis (lower stage, less nodal involvement and metastases, longer survival) [137, 138]; Balint et al. showed no link with tumour size and grade [132]
Chromosome Y	Loss	NA	Affects 71–87% of tumours in men [137, 138, 158, 184]	NA	Loss of chromosome Y not linked to pathological variables and survival [137]
Chromosome X	Loss	NA	Loss involving Xp in 28% and Xq in 36% of pRCC tumours [158]	NA	Losses of chromosome Xp associated with short patient survival [158]
3p	loss	NA	Allelic changes in 14–37.5% of tumours [137, 185]	NA	Loss of 3p associated with higher stage and grade, lymph node involvement, distant metastasis, larger tumour size, and worse survival [137]
Gains of 1q, chromosomes 12, 16, and 20; losses of 1p, 4q, 5q, 6q, 8p, 9p, 11, 13q, 14q, and 18 [135, 137, 138, 158, 186]					Loss of 9p associated with higher stage, larger tumour size, metastasis, lymph node involvement, recurrence, and decreased survival [137, 138]; losses of 8p and chromosome 18 correlated with higher stage, metastasis, and worse recurrence free survival [138]

NA indicates not available.

(c)

Tumour type	Chromosome	Type of genetic alteration	Candidate gene	Incidence	Function of protein	Prognosis
chRCC	Losses at chromosomes 1 (73–90%), 2 (70–90%), 6 (62–96%), 10 (70–91%), 13 (51–86%), 17 (65–90%), and 21 (32–90%) [187–190]; TP53 mutation in sporadic chRCC (24–32%) located at 17p13.1 [191–193]					No relation between chromosomal numerical changes and the Paner grading system [190]
RO	Loss or alterations of 1p (31–86%) [188, 194, 195], chromosomes Y (100% in males) [196] and 14 (15–50%) [188, 197]					NA
	11q13	Translocation	CCND1	CCND1 translocation in 11–36% of ROs [198–200]	Cyclin D1 is involved in the regulation of cell cycle, G1-S phase, and cell proliferation	NA
CDRCC	Reported losses of chromosomes 1, 1p, 6, 8p, 9p, 14, 15, 16p, and 22 and gains in 13q in CDRCC tumours [201, 202]					NA

NA indicates not available.