Somatic alterations contributing to metastasis of a castration-resistant prostate cancer

Hum Mutat. 2013 Sep;34(9):1231-41. doi: 10.1002/humu.22346. Epub 2013 Jun 3.

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) 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 mCRPC to identify lesions associated with disease progression and metastasis. An Ashkenazi Jewish (AJ) germline founder mutation, del185AG 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 mCRPC samples and detected a frameshift, two somatic missense alterations, tumor loss of heterozygosity, and combinations of germline missense SNPs 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 mCRPC deserves additional analysis and may define a subset of metastatic disease.

Keywords: BRCA1; ERG; PBRM1; TET2; TMPRSS2; epigenetic modifiers; metastasis; somatic mutation; tumor heterogeneity.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amino Acid Sequence
  • DNA-Binding Proteins / genetics*
  • Frameshift Mutation
  • Genes, BRCA1*
  • Germ-Line Mutation
  • Humans
  • Loss of Heterozygosity
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation, Missense
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / pathology
  • Nuclear Proteins / genetics*
  • Oncogene Proteins, Fusion / genetics*
  • Phylogeny
  • Polymorphism, Single Nucleotide
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology*
  • Proto-Oncogene Proteins / genetics*
  • Sequence Analysis, DNA
  • Transcription Factors / genetics*

Substances

  • DNA-Binding Proteins
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • PBRM1 protein, human
  • Proto-Oncogene Proteins
  • TET2 protein, human
  • TMPRSS2-ERG fusion protein, human
  • Transcription Factors