Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.
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 rena...
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Public Library of Science (PLoS)
2011-10-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002312&type=printable |
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| author | Lee E Moore Michael L Nickerson Paul Brennan Jorge R Toro Erich Jaeger Jessica Rinsky Summer S Han David Zaridze Vsevolod Matveev Vladimir Janout Hellena Kollarova Vladimir Bencko Marie Navratilova Neonilia Szeszenia-Dabrowska Dana Mates Laura S Schmidt Petra Lenz Sara Karami W Marston Linehan Maria Merino Stephen Chanock Paolo Boffetta Wong-Ho Chow Frederic M Waldman Nathaniel Rothman |
| author_facet | Lee E Moore Michael L Nickerson Paul Brennan Jorge R Toro Erich Jaeger Jessica Rinsky Summer S Han David Zaridze Vsevolod Matveev Vladimir Janout Hellena Kollarova Vladimir Bencko Marie Navratilova Neonilia Szeszenia-Dabrowska Dana Mates Laura S Schmidt Petra Lenz Sara Karami W Marston Linehan Maria Merino Stephen Chanock Paolo Boffetta Wong-Ho Chow Frederic M Waldman Nathaniel Rothman |
| author_sort | Lee E Moore |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bd67a45cf52e4d689d24684d0c06fcef |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2011-10-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-bd67a45cf52e4d689d24684d0c06fcef2025-01-17T05:31:13ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-10-01710e100231210.1371/journal.pgen.1002312Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.Lee E MooreMichael L NickersonPaul BrennanJorge R ToroErich JaegerJessica RinskySummer S HanDavid ZaridzeVsevolod MatveevVladimir JanoutHellena KollarovaVladimir BenckoMarie NavratilovaNeonilia Szeszenia-DabrowskaDana MatesLaura S SchmidtPetra LenzSara KaramiW Marston LinehanMaria MerinoStephen ChanockPaolo BoffettaWong-Ho ChowFrederic M WaldmanNathaniel RothmanRenal 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002312&type=printable |
| spellingShingle | Lee E Moore Michael L Nickerson Paul Brennan Jorge R Toro Erich Jaeger Jessica Rinsky Summer S Han David Zaridze Vsevolod Matveev Vladimir Janout Hellena Kollarova Vladimir Bencko Marie Navratilova Neonilia Szeszenia-Dabrowska Dana Mates Laura S Schmidt Petra Lenz Sara Karami W Marston Linehan Maria Merino Stephen Chanock Paolo Boffetta Wong-Ho Chow Frederic M Waldman Nathaniel Rothman Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. PLoS Genetics |
| title | Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. |
| title_full | Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. |
| title_fullStr | Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. |
| title_full_unstemmed | Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. |
| title_short | Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. |
| title_sort | von hippel lindau vhl inactivation in sporadic clear cell renal cancer associations with germline vhl polymorphisms and etiologic risk factors |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002312&type=printable |
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