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Updated: Sep 7, 2025
miRNA Expression Analyses in Prostate Cancer Clinical Tissues
Published on: September 8, 2015
The tumor mutational landscape of BRCA2-deficient primary and metastatic prostate cancer
Kevin H Kensler1, Shakuntala Baichoo2, Shailja Pathania3,4
1Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
Abstract:
Carriers of germline BRCA2 pathogenic sequence variants have elevated aggressive prostate cancer risk and are candidates for precision oncology treatments. We examined whether BRCA2-deficient (BRCA2d) prostate tumors have distinct genomic alterations compared with BRCA2-intact (BRCA2i) tumors. Among 2536 primary and 899 metastatic prostate tumors from the ICGC, GENIE, and TCGA databases, we identified 138 primary and 85 metastatic BRCA2d tumors. Total tumor mutation burden (TMB) was higher among primary BRCA2d tumors, although pathogenic TMB did not differ by tumor BRCA2 status. Pathogenic and total single nucleotide variant (SNV) frequencies at KMT2D were higher in BRCA2d primary tumors, as was the total SNV frequency at KMT2D in BRCA2d metastatic tumors. Homozygous deletions at NEK3, RB1, and APC were enriched in BRCA2d primary tumors, and RB1 deletions in metastatic BRCA2d tumors as well. TMPRSS2-ETV1 fusions were more common in BRCA2d tumors. These results identify somatic alterations that hallmark etiological and prognostic differences between BRCA2d and BRCA2i prostate tumors.
Insights
Germline BRCA2 variants increase aggressive prostate cancer risk. BRCA2-deficient tumors show distinct genomic changes, including higher mutation burden and specific gene alterations, differentiating them from BRCA2-intact tumors.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Germline BRCA2 pathogenic variants are linked to aggressive prostate cancer.
- Patients with these variants are candidates for precision oncology.
- Understanding tumor-specific genomic alterations is crucial for targeted therapies.
Purpose of the Study:
- To investigate distinct genomic alterations in BRCA2-deficient (BRCA2d) prostate tumors compared to BRCA2-intact (BRCA2i) tumors.
- To identify somatic alterations that characterize etiological and prognostic differences.
Main Methods:
- Analysis of 2536 primary and 899 metastatic prostate tumors from ICGC, GENIE, and TCGA databases.
- Identification of 138 primary and 85 metastatic BRCA2d tumors.
- Comparison of tumor mutation burden (TMB), single nucleotide variant (SNV) frequencies, homozygous deletions, and gene fusions between BRCA2d and BRCA2i tumors.
Main Results:
- BRCA2d primary tumors exhibited higher total tumor mutation burden (TMB).
- Elevated frequencies of KMT2D SNVs and TMPRSS2-ETV1 fusions were observed in BRCA2d tumors.
- Enrichment of homozygous deletions at NEK3, RB1, and APC in BRCA2d primary tumors, and RB1 in metastatic BRCA2d tumors.
Conclusions:
- BRCA2-deficient prostate tumors possess unique genomic profiles.
- Identified somatic alterations serve as hallmarks for etiological and prognostic distinctions.
- These findings support the role of genomic profiling in precision oncology for prostate cancer.
