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Somatic Alterations Contributing to Metastasis of a Castration‐Resistant Prostate Cancer
Author(s) -
Nickerson Michael L.,
Im Kate M.,
Misner Kevin J.,
Tan Wei,
Lou Hong,
Gold Bert,
Wells David W.,
Bravo Hector C.,
Fredrikson Karin M.,
Harkins Timothy T.,
Milos Patrice,
Zbar Berton,
Linehan W. Marston,
Yeager Meredith,
Andresson Thorkell,
Dean Michael,
Bova G. Steven
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22346
Subject(s) - biology , loss of heterozygosity , germline , missense mutation , somatic cell , prostate cancer , germline mutation , frameshift mutation , metastasis , exome , exome sequencing , genetics , somatic evolution in cancer , cancer research , cancer , mutation , gene , allele
Metastatic castration‐resistant prostate cancer (m CRPC ) is a lethal disease, and molecular markers that differentiate indolent from aggressive subtypes are needed. We sequenced the exomes of five metastatic tumors and healthy kidney tissue from an index case with m CRPC to identify lesions associated with disease progression and metastasis. An A shkenazi J ewish ( AJ ) germline founder mutation, del185 AG in BRCA1 , was observed and AJ ancestry was confirmed. Sixty‐two somatic variants altered proteins in tumors, including cancer‐associated genes, TMPRSS2‐ERG , PBRM1 , and TET2 . The majority ( n = 53) of somatic variants were present in all metastases and only a subset ( n = 31) was observed in the primary tumor. Integrating tumor next‐generation sequencing and DNA copy number showed somatic loss of BRCA1 and TMPRSS2‐ERG . We sequenced 19 genes with deleterious mutations in the index case in additional m CRPC samples and detected a frameshift, two somatic missense alterations, tumor loss of heterozygosity, and combinations of germline missense SNP s in TET2 . In summary, genetic analysis of metastases from an index case permitted us to infer a chronology for the clonal spread of disease based on sequential accrual of somatic lesions. The role of TET2 in m CRPC deserves additional analysis and may define a subset of metastatic disease.