High burden of copy number alterations and c-MYC amplification in prostate cancer from BRCA2 germline mutation carriers

E. Castro*, S. Jugurnauth-Little, Q. Karlsson, F. Al-Shahrour, E. Pineiro-Yanez, F. Van de Poll, D. Leongamornlert, T. Dadaev, K. Govindasami, M. Guy, R. Eeles, Z. Kote-Jarai, UKGPCS Study, EMBRACE Study, IMPACT Study

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Scopus)

Abstract

Background: Germline BRCA2 mutations are associated with poorer outcome prostate cancer ( PCa) compared with sporadic tumours but this association remains to be characterised. In this study, we aim to assess if there is a signature set of copy number alterations ( CNA) that could aid to the identification of BRCA2- mutated tumours and would assist us to understand their aggressive clinical behaviour. Methods: High- resolution array comparative genomic hybridisation profiling of DNA from PCa and matched morphologically normal prostate samples from 9 BRCA2 germline mutation carriers and 16 non- carriers in combination with unsupervised analysis was used to define copy number features. Results: PCa from BRCA2 germline mutation carriers ( B2T) harbour significantly more CNA than non- carrier tumours ( NCTs) ( P = 14 x 10(-6)). A hundred and sixteen regions had a significantly different distribution with both false discovery rate ( FDR) and P value <0.01, including CNA in the genomic region containing c- MYC that was present in 89% B2T versus 12.5% NCT ( P = 3 x 10(-4)). Loss of heterozygosity ( LOH) at the BRCA2 locus was observed in 67% of B2T. Elevated CNA are already present in 50% of the morphologically normal prostate tissue from BRCA2 carriers. Conclusion: The relative high amount of CNAs in morphologically normal prostate tissue of BRCA2 carriers implies a field effect and together with the observed LOH could be used as a marker of PCa risk in these men. Several features previously associated with poor PCa outcome have been found to be significantly more common in BRCA2- mutated PCa than in sporadic tumours and may help to explain their adverse prognosis and be of relevance for targeted therapies.

Original languageEnglish
Pages (from-to)2293-2300
Number of pages8
JournalAnnals of Oncology
Volume26
Issue number11
DOIs
Publication statusPublished - Nov-2015

Keywords

  • prostate cancer
  • germline
  • BRCA2
  • CNV
  • c-MYC
  • LOH
  • COMPARATIVE GENOMIC HYBRIDIZATION
  • EPITHELIAL OVARIAN-CANCER
  • BRCANESS
  • RELAPSE
  • HETEROZYGOSITY
  • SUSCEPTIBILITY
  • PROGRESSION
  • EXPRESSION
  • SURVIVAL
  • LOCUS

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