Accumulation of cancer driver gene mutations during progression of metastatic prostate cancer

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NCI	GEN/GENOM-13

Authors

• M Nickerson
• K Im
• K Misner
• A Yates
• D Wells
• H Bravo
• K Fredrikson
• W Tan
• M Yeager
• B Zbar
• M Dean
• S Bova

Abstract

Metastatic prostate cancer is a highly morbid condition, poorly controlled using existing therapies. Prostate cancer may progress to metastatic disease through several stages, but the precise molecular ontology of the disease remains unknown. Exome sequencing of five metastatic tumors and non-cancerous tissue from a prostate cancer patient was performed to examine somatic alterations arising during metastatic spread of cancer. We validated novel alterations and explored candidate cancer metastasis genes by PCR and Sanger sequencing. A germline BRCA1 mutation and sixty-two somatic nonsynonymous variants were observed, including alterations of known cancer genes, PBRM1, TMPRSS2, and TET2. A subset of somatic variants were detected in primary prostate adenocarcinoma and were considered candidate cancer initiating genes; and 31 somatic variants were observed in all metastatic deposits and were considered candidate metastasis genes, including TMPRSS2 and TET2. Nine variants present in single tumors allowing the sequential spread of cancer to be mapped. Examination of these genes in prostate tumors from additional patients revealed somatic alterations of TET2. These results suggest dysregulated epigenetic modifications of chromatin and DNA may play a role in metastatic prostate cancer. The utility of exome sequencing for genetic dissection of cancer and for personalized medicine is demonstrated.

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