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MED12L Gene Alterations Define Aggressive BRCA2-Mutant Prostate Cancers

Germline mutation of BRCA2 increases the lifetime risk of developing prostate cancer (PCa) by over 700%. BRCA2-mutant PCa have poorer prognosis than sporadic PCa, with rapid development of metastatic, castrate-resistant prostate cancer (mCRPC) and 5-year cancer-specific survival rates of ~50-60%1-4. Despite this, unique genomic driver events that explain the aggressiveness of localized BRCA2-mutant PCa are lacking. We used whole-genome sequencing to fully characterize 14 BRCA2-mutant PCa and demonstrate that BRCA2-mutant PCa is associated with increased genetic instability and a mutually exclusive mutational burden when compared to sporadic PCa. Importantly, BRCA2-mutated cancers are defined by unique copy number gains and hypomethylation events, including alterations in the MED12L/MED12 axis, which are found solely in mCRPC and are enriched in PCa tumours harbouring aggressive intraductal carcinoma (IDC-P) pathologic sub-types. Our findings begin to explain the clinical entity of BRCA2-mutated PCa as these tumours have a unique and aggressive genotype de novo, associated with IDC-P and mCRPC, even in the hormone-naive setting.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001002739 49
EGAD00001003752 34
EGAD00001003753 20
EGAD00001003754 37
EGAD00010001196 Affymetrix OncoScan FFPE Express 48
Publications Citations
Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.
Nat Commun 8: 2017 13671
Quantifying the influence of mutation detection on tumour subclonal reconstruction.
Nat Commun 11: 2020 6247