An analysis of the association between prostate cancer risk loci, PSA levels, disease aggressiveness and disease-specific mortality.

BACKGROUND - Genome-wide association studies have identified multiple single-nucleotide polymorphsims (SNPs) associated with prostate cancer (PCa). Although these SNPs have been clearly associated with disease risk, their relationship with clinical outcomes is less clear. Our aim was to assess the frequency of known PCa susceptibility alleles within a single institution ascertainment and to correlate risk alleles with disease-specific outcomes.

METHODS - We genotyped 1354 individuals treated for localised PCa between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to phenotypic data. We investigated associations between 61 SNPs and disease-specific end points using multivariable analysis and also determined if SNPs were associated with PSA at diagnosis.

RESULTS - Seven SNPs showed associations on multivariable analysis (P<0.05), rs13385191 with both biochemical recurrence (BR) and castrate metastasis (CM), rs339331 (BR), rs1894292, rs17178655 and rs11067228 (CM), and rs11902236 and rs4857841 PCa-specific mortality. After applying a Bonferroni correction for number of SNPs (P<0.0008), the only persistent significant association was between rs17632542 (KLK3) and PSA levels at diagnosis (P=1.4 × 10(-5)).

CONCLUSIONS - We confirmed that rs17632542 in KLK3 is associated with PSA at diagnosis. No significant association was seen between loci and disease-specific end points when accounting for multiple testing. This provides further evidence that known PCa risk SNPs do not predict likelihood of disease progression.

Br J Cancer. 2015 Jun 30;113(1):166-72. doi: 10.1038/bjc.2015.199. Epub 2015 Jun 11.

Sullivan J1, Kopp R1, Stratton K1, Manschreck C2, Corines M2, Rau-Murthy R2, Hayes J2, Lincon A2, Ashraf A2, Thomas T2, Schrader K2, Gallagher D2, Hamilton R2, Scher H3, Lilja H4, Scardino P4, Eastham J4, Offit K2, Vijai J2, Klein RJ5.

1 1] Department of Medicine, Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
2 Department of Medicine, Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
3 Department of Medicine, Genitourinary Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
4 Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
5 1] Department of Medicine, Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.