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


CONCLUSIONS
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.
Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain Oncogenetics Team, The Institute of Cancer Research, London, UK ecastro@cnio.es.
E
E
Castro
Oncogenetics Team, The Institute of Cancer Research, London, UK.
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S
Jugurnauth-Little
Oncogenetics Team, The Institute of Cancer Research, London, UK.
Q
Q
Karlsson
Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre, Madrid, Spain.
F
F
Al-Shahrour
Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre, Madrid, Spain.
E
E
Piñeiro-Yañez
Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain.
F
F
Van de Poll
Oncogenetics Team, The Institute of Cancer Research, London, UK.
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D
Leongamornlert
Oncogenetics Team, The Institute of Cancer Research, London, UK.
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T
Dadaev
Oncogenetics Team, The Institute of Cancer Research, London, UK.
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K
Govindasami
Oncogenetics Team, The Institute of Cancer Research, London, UK.
M
M
Guy
Oncogenetics Team, The Institute of Cancer Research, London, UK The Royal Marsden NHS Foundation Trust, London, UK.
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R
Eeles
Oncogenetics Team, The Institute of Cancer Research, London, UK.
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Z
Kote-Jarai
D000328:Adult; D000368:Aged; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*
D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc
BRCA2; CNV; LOH; c-MYC; germline; prostate cancer