High burden of copy number alterations and c-MYC amplification in prostate cancer from BRCA2 germline mutation carriers
A partir d'échantillons de tissu tumoral et de tissu sain prélevés sur 25 patients atteints d'un cancer de la prostate (dont 9 porteurs de mutations constitutionnelles du gène BRCA2), cette étude analyse les anomalies du nombre de copies de gènes en fonction de la présence d'un gène BRCA2 muté
Background : Germline BRCA2 mutations are associated with poorer outcome prostate cancer (PCa) compared with sporadic tumours but this association remains to be characterized. 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 comparative genomic hybridization (aCGH) 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-mutated tumours (NCT) (p=14x10−6). 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 vs 12.5% NCT (p=3x10−4). 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.