Abstract
INTRODUCTION AND OBJECTIVES: The ability to predict disease aggressiveness using inherited markers such as single nucleotide polymorphisms (SNPs) would be invaluable, allowing clinicians to tailor treatment according to risks. However, the majority of validated prostate cancer (PC) risk SNPs have not been conclusively linked to disease aggressiveness or evaluated in an active surveillance (AS) cohort. Recently, it was documented that there were associations between some of the 23 newly discovered iCOGS SNPs and aspects of disease aggressiveness (Nat Genet. 2013. 45: 385). However, the utility of these iCOGS SNPs remains to be determined in AS. METHODS: The genotypes of the 23 iCOGS SNPs were determined for all Caucasian subjects with biopsy Gleason score (GS) 1⁄4 6, including 1177 men who underwent definitive treatment with surgery and 140 men who elected AS. The clinical and pathologic characteristics were documented for all subjects. Men who underwent surgery were grouped according to their pathologic GS (upgraded was defined as GS 7; non-upgraded remained GS1⁄46). Men who were enrolled in AS were also grouped according to their GS on subsequent surveillance biopsies. Statistical analyses were initially performed in the surgical cohort comparing the genotypes between the up-graded and non-upgraded groups. These findings were validated within the AS cohort. RESULTS: Overall, 32% and 42% of men were upgraded in the surgery and AS cohorts, respectively. Table 1 shows that 3 iCOGS SNPs were significantly associated with the risk of upgrading in the surgical cohort. After correction for multiple testing, only rs1158818 on chromosome 11q22 remained significantly associated with upgrading. Assessment of this allele in the AS cohort reveals that it was present at significantly higher frequencies in men with highgrade disease on surveillance biopsies compared to non-upgraded men (p1⁄40.04). CONCLUSIONS: Novel genetic biomarkers that can help improve PC screening and treatment decisions are needed. This is the first report of a SNP on chromosome 11q22 that is associated with higher grade disease in a surgical cohort that is also validated for “progression” in a prospective AS cohort. Similar validation studies of these associations with aggressive disease are warranted.
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