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Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: Associations with germline VHL polymorphisms and etiologic risk factors
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نویسنده
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moore l.e. ,nickerson m.l. ,brennan p. ,toro j.r. ,jaeger e. ,rinsky j. ,han s.s. ,zaridze d. ,matveev v. ,janout v. ,kollarova h. ,bencko v. ,navratilova m. ,szeszenia-dabrowska n. ,mates d. ,schmidt l.s. ,lenz p. ,karami s. ,linehan w.m. ,merino m. ,chanock s. ,boffetta p. ,chow w.-h. ,waldman f.m. ,rothman n.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 10
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چکیده
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Renal tumor heterogeneity studies have utilized the von hippel-lindau vhl gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. the aim of this study was to provide a comprehensive analysis of vhl inactivation in clear cell renal tumors (ccrcc) and to evaluate relationships between vhl inactivation subgroups with renal cancer risk factors and vhl germline single nucleotide polymorphisms (snps). vhl genetic and epigenetic inactivation was examined among 507 sporadic rcc/470 ccrcc cases using endonuclease scanning and using bisulfite treatment and sanger sequencing across 11 cpg sites within the vhl promoter. case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. vhl inactivation,either through sequence alterations or promoter methylation in tumor dna,was observed among 86.6% of ccrcc cases. germline vhl snps and a haplotype were associated with promoter hypermethylation in tumor tissue (or = 6.10; 95% ci: 2.28-16.35,p = 3.76e-4,p-global = 8e-5). risk of having genetic vhl inactivation was inversely associated with smoking due to a higher proportion of wild-type ccrcc tumors [former: or = 0.70 (0.20-1.31) and current: or = 0.56 (0.32-0.99); p-trend = 0.04]. alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccrcc cases with particular vhl germline polymorphisms were more likely to have vhl inactivation through promoter hypermethylation than through sequence alterations in tumor dna,suggesting that the presence of these snps may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation) in renal tissue. a proportion of tumors from current smokers lacked vhl alterations and may represent a biologically distinct clinical entity from inactivated cases.
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آدرس
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division of cancer epidemiology and genetics,national cancer institute,national institutes of health,bethesda,md, United States, cancer and inflammation program,national cancer institute,frederick,md, United States, international agency for research on cancer,lyon, France, division of cancer epidemiology and genetics,national cancer institute,national institutes of health,bethesda,md, United States, university of california san francisco,san francisco,ca, United States, division of cancer epidemiology and genetics,national cancer institute,national institutes of health,bethesda,md, United States, division of cancer epidemiology and genetics,national cancer institute,national institutes of health,bethesda,md, United States, institute of carcinogenesis,cancer research centre,moscow, Russian Federation, institute of carcinogenesis,cancer research centre,moscow, Russian Federation, department of preventive medicine,faculty of medicine,palacky university,olomouc, Czech Republic, department of preventive medicine,faculty of medicine,palacky university,olomouc, Czech Republic, institute of hygiene and epidemiology,charles university,prague, Czech Republic, department of cancer epidemiology and genetics,masaryk memorial cancer institute,brno, Czech Republic, department of epidemiology,institute of occupational medicine,lodz, Poland, institute of public health,bucharest, Romania, basic science program,saic-frederick,nci-frederick,frederick,md,united states,urologic oncology branch,national cancer institute,national institutes of health,bethesda,md, United States, support to the division of cancer epidemiology and genetics,national cancer institute,saic-frederick,nci- frederick,frederick,md, United States, division of cancer epidemiology and genetics,national cancer institute,national institutes of health,bethesda,md, United States, urologic oncology branch,national cancer institute,national institutes of health,bethesda,md, United States, support to the division of cancer epidemiology and genetics,national cancer institute,saic-frederick,nci- frederick,frederick,md, United States, division of cancer epidemiology and genetics,national cancer institute,national institutes of health,bethesda,md,united states,advanced technology center of the national cancer institute,national institutes of health,department of health and human services,bethesda,md, United States, cancer and inflammation program,national cancer institute,frederick,md,united states,the tisch cancer institute,mount sinai school of medicine,new york,ny,united states,international cancer prevention research institute,lyon, France, division of cancer epidemiology and genetics,national cancer institute,national institutes of health,bethesda,md, United States, university of california san francisco,san francisco,ca, United States, division of cancer epidemiology and genetics,national cancer institute,national institutes of health,bethesda,md, United States
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Authors
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