Identification of Genes with Rare Loss of Function Variants Associated with Aggressive Prostate Cancer and Survival

Area of Science:

• Genetics
• Oncology
• Genomic Medicine

Background:

• Prostate cancer (PrCa) is a leading cause of cancer mortality in men worldwide.
• Germline mutations in BRCA2 are known risk factors for aggressive PrCa, but the role of other genes is less clear.

Purpose of the Study:

• To identify genes associated with PrCa aggressiveness using pooled rare variant sequencing data.
• To analyze data from the UK Genetic Prostate Cancer Study (UKGPCS) across six previous studies.

Main Methods:

• A cohort of 6805 PrCa cases was analyzed.
• Ten candidate genes were sequenced in all samples.
• Rare putative loss-of-function (pLOF) variants were examined for association with aggressive PrCa classification.

Main Results:

• pLOF mutations in ATM, BRCA2, MSH2, and NBN were significantly associated with PrCa aggressiveness (OR = 2.67–18.9).
• These genes, along with MLH1, were linked to specific secondary phenotypes.
• Carriers of these germline mutations had significantly shorter PrCa-specific survival (HR = 2.15).

Conclusions:

• Rare pLOF variants in ATM, BRCA2, MSH2, and NBN are strongly associated with increased risk of aggressive PrCa.
• These findings support the use of specific gene panels for PrCa screening and treatment decisions.
• Identifying men with these mutations can aid in predicting elevated risk of PrCa mortality.