title: Common variation in BRCA1 may have a role in progression to lethal prostate cancer after radiation treatment.
abstract: To evaluate whether single-nucleotide polymorphisms (SNPs) reflecting common variation in the tumor suppressor BRCA1 affect prostate cancer outcomes. Because radiation therapy (RT) induces DNA damage, we hypothesized that common variation in BRCA1 has a role in progression to lethal prostate cancer, particularly in patients receiving RT.
  
  
  
  We followed 802 men diagnosed with localized prostate cancer (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 prostate cancer. Six SNPs (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.
  
  
  
  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 prostate cancer in men receiving RT.
  
  
  
  Common variation in BRCA1 may influence clinical outcomes in patients receiving RT for localized prostate cancer 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.
authors.affiliation: Department of Urology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sanchez
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Schoenfeld
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Nguyen
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Fiorentino
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Chowdhury
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.|Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Stampfer
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.|Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: H D
authors.initials: HD
authors.lastname: Sesso
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Giovannucci
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Mucci
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.|Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Shui
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D019313:BRCA1 Protein / Q000235:genetics*; D003131:Combined Modality Therapy; D004249:DNA Damage; D018450:Disease Progression; D005500:Follow-Up Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy
chemical_list: D019313:BRCA1 Protein