Genomic copy number alterations in clear cell renal carcinoma: associations with case characteristics and mechanisms of VHL gene inactivation - PubMed (original) (raw)
doi: 10.1038/oncsis.2012.14.
E Jaeger, M L Nickerson, P Brennan, S De Vries, R Roy, J Toro, H Li, S Karami, P Lenz, D Zaridze, V Janout, V Bencko, M Navratilova, N Szeszenia-Dabrowska, D Mates, W M Linehan, M Merino, J Simko, R Pfeiffer, P Boffetta, S Hewitt, N Rothman, W-H Chow, F M Waldman
Affiliations
- PMID: 23552698
- PMCID: PMC3412648
- DOI: 10.1038/oncsis.2012.14
Genomic copy number alterations in clear cell renal carcinoma: associations with case characteristics and mechanisms of VHL gene inactivation
L E Moore et al. Oncogenesis. 2012.
Abstract
Array comparative genomic hybridization was used to identify copy number alterations in clear cell renal cell carcinoma (ccRCC) patient tumors to identify associations with patient/clinical characteristics. Of 763 ccRCC patients, 412 (54%) provided frozen biopsies. Clones were analyzed for significant copy number differences, adjusting for multiple comparisons and covariates in multivariate analyses. Frequent alterations included losses on: 3p (92.2%), 14q (46.8%), 8p (38.1%), 4q (35.4%), 9p (32.3%), 9q (31.8%), 6q (30.8%), 3q (29.4%), 10q (25.7%), 13q (24.5%), 1p (23.5%) and gains on 5q (60.2%), 7q (39.6%), 7p (30.6%), 5p (26.5%), 20q (25.5%), 12q (24.8%), 12p (22.8%). Stage and grade were associated with 1p, 9p, 9q, 13q and 14q loss and 12q gain. Males had more alterations compared with females, independent of stage and grade. Significant differences in the number/types of alterations were observed by family cancer history, age at diagnosis and smoking status. Von Hippel-Lindau (VHL) gene inactivation was associated with 3p loss (P<E-05), and these cases had fewer alterations than wild-type cases. The fragile site flanking the FHIT locus (3p14.2) represented a unique breakpoint among VHL hypermethylated cases, compared with wild-type cases and those with sequence changes. This is the first study of its size to investigate copy number alterations among cases with extensive patient, clinical/risk factor information. Patients characterized by VHL wild-type gene status (vs sequence alterations) and male (vs female) cases had more copy number alterations regardless of diagnostic stage and grade, which could relate to poor prognosis.
Figures
Figure 1
Fraction (%) of the FGL, FGG and FGA among ccRCC case subgroups. _P_-values between subgroups were as follows: males vs females (_P_=0.002), age (<50, vs ⩾50 years, _P_=0.06), any family history of cancer (_P_=0.02), stage (P<0.00001), grade (P<0.0001), ever vs never smoking (_P_=0.05), VHL wild-type cases vs those with VHL promoter hypermethylation (_P_=0.03), VHL wild-type cases vs those with VHL sequence alterations (_P_=0.17). REF, referent group.
Figure 2
Frequency of copy number loss of 3p clones among ccRCC cases grouped by absence (wild-type) or presence of VHL gene inactivation (through sequence alteration or promoter hypermethylation). Region A (telomere to RP11-180G14): the frequency of copy number loss of individual 3p clones differed significantly between VHL wild-type and inactivated cases that occurred through both sequence alteration (P<0.00001) and promoter hypermethylation (_P_=0.03–0.001). Region B (from RP11-180G14to RP11-154H23): the frequency of clonal copy number loss differed significantly between wild-type cases and those with sequence alterations (_P_=0.003–<0.00001), but was no longer observed with hypermethylated cases (_P_=0.08–0.59).
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