Common variation in BRCA1 may have a role in progression to lethal prostate cancer after radiation treatment

Abstract

Purpose To evaluate if single-nucleotide polymorphisms (SNPs) reflecting common variation in the tumor suppressor BRCA1 affects prostate cancer (CaP) outcomes. Because radiation therapy (RT) induces DNA damage, we hypothesized that common variation in BRCA1 plays a role in progression to lethal CaP, particularly in patients receiving RT. Methods We followed 802 men diagnosed with localized CaP (cT1-T3/N0/M0) who were treated with RT in the US Health Professionals Follow-up Study (HPFS) and Physicians’ Health Study (PHS), for progression to lethal CaP. Six single-nucleotide polymorphisms (rs3737559, rs1799950, rs799923, rs915945, rs4474733, and rs8176305) were genotyped in HPFS to capture common variation across BRCA1. rs4474733 and rs8176305 were also evaluated in the PHS cohort. Cox proportional hazards models were used to estimate per-allele hazard ratios (HR) and 95% confidence intervals (CI) stratified by primary treatment. Results In the RT group (n=802) 71 men progressed to lethal disease during a mean follow-up of 12 years. We found that two SNPs, rs4473733 (HR: 0.65; 95%CI 0.42-0.99) and rs8176305 (HR: 2.03; 95%CI 1.33-3.10), were associated with lethal CaP in men receiving RT. Conclusions Common variation in BRCA1 may influence clinical outcomes in patients receiving RT for localized CaP by modifying the response to RT. Our findings merit further follow-up studies to validate these SNPs and better understand their functional and biological significance.

Identification of Variants (rs11571707, rs144848, and rs11571769) in the BRCA2 Gene Associated with Hereditary Breast Cancer in Indigenous Populations of the Brazilian Amazon

“…Among the eight single nucleotide polymorphisms (SNP) of the BRCA1 gene, the rs799923, rs1799966 and rs799917 have been associated with the increased risk of BC in Asians [ 22 , 23 ]. In contrast, the rs16942 and rs1799949 variants have been associated with the predisposition to BC in the African population [ 24 , 25 ].…”

A Review of Prostate Cancer Genome-Wide Association Studies (GWAS)

“…As well as markers of radiotoxicity, identification of patients less likely to respond to radiation would guide decision making early on in the curative treatment pathway for localised PrCa. In a study of common variants of the BRCA1 gene in men who underwent definitive treatment for localised PrCa, two BRCA1 SNPs were found to have a significant association with lethal PrCa after RT:[44] rs4474733 was associated with a 35% lower risk of lethal PrCa and rs8176305 was associated with a two-fold increased risk of lethal PrCa. There was no significant association observed in men treated with surgery.…”

Effect of DNA Damage Response Mutations on Prostate Cancer Prognosis: A Systematic Review

“…Three studies were identified for the UK: one included patients with PC [24], one included mCRPC [6] and one included primary PC [30]. 12 studies were identified for the USA: four included PC [35,38], four included mCRPC [39,40,44] (one of which also required patients to express androgen receptor variant 7) [43], one included mPC [46], one included both primary PC and CRPC [48] and two included primary PC [50,51]. Three studies were multinational: two included mCRPC [53,55] and one included CRPC [59].…”

“…Of the 26 included studies, interventions were separated into drug-based treatments (12 studies) [6,17,18,20,39,40,43,44,46,53,55,57], non-drug-based treatments (11 studies) [14,19,21,22,30,34,[36][37][38]50,51] and mixed treatments (three studies) [15,24,48].…”