BRCA2-mutated prostatic adenocarcinoma

Phenotype

 IDCP : intraductal carcinoma of the prostate
 Associations :

• high-grade tumor
• large tumor volume
• poor clinical outcome

The carrier rate of germline BRCA1/2 and ATM mutation was ∼5-fold higher in lethal prostate cancer patients than in localized prostate cancer patients. doi : 10.1016/j.eururo.2016.11.033

Mutation carriers of BRCA1/2 and ATM are associated with earlier age at death and shorter survival time. doi : 10.1016/j.eururo.2016.11.033

Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease.

Germline mutation of the BRCA2 tumour suppressor gene substantially increases the lifetime risk of developing prostate cancer (PCa).

In BRCA2-mutation carriers, localized PCa rapidly progresses to metastatic castrate-resistant prostate cancer (mCRPC) with 5-year cancer-specific survival rates of ∼50–60%.

BRCA2-mutant tumours also exhibit an increased frequency of intraductal carcinoma (IDC), a pathology that predicts adverse outcome in both familial5 and sporadic PCa.

Prostate tumours arising in men with an inactivating BRCA2 germline mutation (BRCA2-mutant PCa) are uniquely aggressive, associated with younger age of onset, have higher rates of lymph node and distant metastasis, and increased mortality relative to sporadic, non-BRCA2-mutant disease.

Precision surgery or radiotherapy with curative intent inexplicably fails, with a rapid onset of incurable mCRPC in BRCA2-mutant PCa.

The molecular origins of the clinical aggressiveness of BRCA2-mutant PCa are unknown. Understanding them may allow better treatment decision-making; for example, given their DNA repair deficient genotype, these cancers may be amenable to treatment with PARP inhibitors, based on genetic synthetic lethality.

Localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.

See also

 BRCAs-associated prostatic adenocarcinoma
 ATM-associated prostatic adenocarcinoma

Open references

 Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. Nature Communications 8, Article number: 13671 (2017)
doi : 10.1038/ncomms13671 Free