Details

Autor(en) / Beteiligte

• Karyadi, Danielle M.
• Zhao, Shanshan
• He, Qianchuan
• McIntosh, Laura
• Wright, Jonathan L.
• Ostrander, Elaine A.
• Feng, Ziding
• Stanford, Janet L.

Titel

Confirmation of genetic variants associated with lethal prostate cancer in a cohort of men from hereditary prostate cancer families

Ist Teil von

• International journal of cancer, 2015-05, Vol.136 (9), p.2166-2171

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• Germline genetic variants have been suggested as prognostic biomarkers for identifying patients at high risk for lethal prostate cancer (PCa). Validation studies have confirmed the association of several single nucleotide polymorphisms (SNPs) with fatal PCa, but whether these variants affect PCa‐specific mortality (PCSM) in patients with an inherited predisposition to PCa, based on familial history, is unknown. For this study, a cohort of 957 PCa patients from 270 hereditary prostate cancer families of European ancestry was genotyped for a panel of 22 PCSM‐associated SNPs. Death certificates were reviewed to confirm cause of death. Mixed‐effect Cox proportional hazards models were used to assess survival according to genotypes, accounting for relatedness and clinicopathological factors. Within this cohort, 98 PCa deaths were confirmed over an average follow‐up period of 12.7 years after diagnosis. Variant allele carriers for three SNPs had significantly altered risk for PCSM [rs635261 at RNASEL, hazard ratio (HR), 0.35, 95% CI, 0.18–0.66; p = 0.002; rs915927 in XRCC1, HR, 1.91, 95% CI, 1.21–3.02; p = 0.009; and rs2494750 at AKT1, HR, 0.45, 95% CI, 0.23–0.90; p = 0.016). These results confirm the association of genetic variation in three genes with PCa lethality in a cohort of men with an inherited susceptibility to the disease and provide validation evidence that germline SNPs provide prognostic information for PCa patients. Development of a panel of germline biomarkers with clinical utility for distinguishing patients at detection who have an increased risk for fatal PCa is warranted. What's new? Genetic variants involved in prostate cancer are promising candidate biomarkers of clinical outcome, particularly mortality. Previous investigation identified 22 germline variants associated with lethal prostate cancer. Here, analysis of those variants in high‐risk patients from families with hereditary prostate cancer validates the association of three single nucleotide polymorphisms (SNPs) with lethal disease. The validated SNPs were located in the genes RNASEL, XRCC1, and AKT1. The findings indicate that germline SNPs may provide prognostic information for distinguishing patients who are at increased risk for progression to fatal prostate cancer.