Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma. Issue 1 (29th October 2013)

• Record Type: Journal Article
• Authors: Gossage, Lucy; Murtaza, Muhammed; Slatter, Andrew F.; Lichtenstein, Conrad P.; Warren, Anne; Haynes, Beverley; Marass, Francesco; Roberts, Ian; Shanahan, Susan J.; Claas, Andreas; Dunham, Andrew; May, Andrew P.; Rosenfeld, Nitzan; Forshew, Tim; Eisen, Tim
• Is Part Of: Genes, chromosomes & cancer. Volume 53:Issue 1(2014:Jan.)
• Page Start: 38
• Page End: 51
• Publication Date: 2013-10-29
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22116
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p> <italic>VHL</italic> is mutated in the majority of patients with clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent studies have identified recurrent mutations in histone modifying and chromatin remodeling genes, including <italic>BAP1, PBRM1, SETD2, KDM6A</italic>, and <italic>JARID1c</italic>. Current evidence suggests that <italic>BAP1</italic> mutations are associated with aggressive disease. The clinical significance of the remaining genes is unknown. In this study, targeted sequencing of <italic>VHL</italic> and <italic>JARID1c</italic> (entire genes) and coding regions of <italic>BAP1, PBRM1, SETD2</italic>, and <italic>KDM6A</italic> was performed on 132 ccRCCs and matched normal tissues. Associations between mutations and clinical and pathological outcomes were interrogated. Inactivation of <italic>VHL</italic> (coding mutation or promoter methylation) was seen in 75% of ccRCCs. Somatic noncoding <italic>VHL</italic> alterations were identified in 29% of ccRCCs and may be associated with improved overall survival. <italic>BAP1</italic> (11%), <italic>PBRM1</italic> (33%), <italic>SETD2</italic> (16%), <italic>JARID1c</italic> (4%), and <italic>KDM6A</italic> (3%) mutations were identified. <italic>BAP1</italic>‐mutated tumors were associated with metastatic disease at presentation (<italic>P</italic> = 0.023), advanced clinical stage (<italic>P</italic> = 0.042) and a trend towards shorter recurrence free survival (<italic>P</italic> = 0.059) when compared with tumors exclusively mutated for <italic>PBRM1</italic>. Our results support those of recent publications pointing towards a role for <italic>BAP1</italic> and <italic>PBRM1</italic> mutations in risk stratifying ccRCCs. Further investigation of noncoding alterations in <italic>VHL</italic> is warranted. © 2013 Wiley Periodicals, Inc.</p> </abstract>