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

Castro, E., Jugurnauth-Little, S., Karlsson, Q., Al-Shahrour, F., Pineiro-Yanez, E., Van de Poll, F., Leongamornlert, D., Dadaev, T., Govindasami, K., Guy, M., Eeles, R., Kote-Jarai, Z., UKGPCS Study, EMBRACE Study & IMPACT Study, Nov-2015, In : Annals of Oncology. 26, 11, p. 2293-2300 8 p.

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  • High burden of copy number alterations and c-MYC amplification

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DOI

  • 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

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
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

ID: 34677680