Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.
Renea A Taylor1, Michael Fraser2, Julie Livingstone3
1Monash Partners Comprehensive Cancer Consortium and Cancer Program, Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, Victoria 3800, Australia.
Nature Communications
|January 10, 2017
Summary
Germline BRCA2 mutations significantly increase prostate cancer (PCa) risk and aggression. BRCA2-mutant PCa exhibits genomic instability and early dysregulation of metastatic-associated genes, necessitating aggressive initial treatment.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Germline BRCA2 mutations are linked to higher prostate cancer (PCa) risk and more aggressive disease.
- Understanding the molecular basis of this aggression in localized PCa is crucial for effective treatment strategies.
Purpose of the Study:
- To investigate the genomic and epigenomic profiles of localized PCa in BRCA2 mutation carriers.
- To identify molecular features contributing to the aggressive nature of BRCA2-mutant PCa.
Main Methods:
- Genome and methylome profiling of localized PCa from 14 BRCA2 mutation carriers.
- Microdissection and sequencing of intraductal carcinoma (IDC) and adjacent invasive carcinoma in 10 patients.
Main Results:
- BRCA2-mutant PCa displays increased genomic instability and a mutational profile resembling metastatic disease.
- Genomic and epigenomic dysregulation of the MED12L/MED12 axis is observed, particularly in tumors with IDC.
- IDC and adjacent invasive carcinoma share a common ancestral origin.
Conclusions:
- Localized, castration-sensitive BRCA2-mutant prostate tumors are uniquely aggressive.
- De novo aberrations in genes typically associated with metastatic disease drive this aggression.
- Aggressive initial treatment is warranted for BRCA2-mutant PCa.
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