Polymorphisms in fragile histidine triad gene (FHIT) associated with aggressive prostate cancer and cancer specific mortality.

Abstract

4646 Background: FHIT is a 1.5 Mb gene encoding a 16.8 kD triphosphatase known to promote apoptosis responding to DNA damage in epithelial cells. It resides in the most frequently observed fragile site in the human genome, FRA3B, and is frequently deleted in early development of multiple cancer types. More importantly, down regulation of FHIT protein has been associated with clinical features of tumors, such as the presence of extraprostatic extension and Gleason Score > 8 in prostate cancer (CaP), advanced diseases in breast cancer, and shorter survival after platinum-based treatment for advanced non-small cell lung cancer. Previously, a genetic locus for CaP has been reported in FHIT. Here we evaluated association of aggressive CaP and death due to CaP with Single nucleotide polymorphisms (SNPs) in FHIT using cases and controls of European origin nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial with 13 years of follow-up. Methods: We analyzed 659 SNPs on FHIT in 1,164 CaP patients (476 with nonaggressive CaP, Gleason < 7 and stage < III; 688 with aggressive CaP, Gleason >= 7 and/or stage III/IV; 63 with death due to CaP) and 1,167 controls using an incidence density sampling strategy. Stratified Cochran-Mantel-Haenszel test and logistic regression were performed to test association. Results: We detected significant association (p < 0.05) of incident CaP to 48 SNPs and aggressive CaP to 52 SNPs. After 50,000 permutations, two SNPs within a 7 kb region, one for incident CaP and the other for aggressive CaP, remained marginally significant (corrected p = 0.053 and 0.093, respectively). The same risk allele for aggressive CaP was also associated with CaP-specific mortality (OR = 1.50, p = 0.027). The association was stronger after adjusting for Gleason, stage, and PSA at diagnosis, treatment options after diagnosis. Test on imputed SNPs within the 7 kb intronic region identified 7 additional SNPs in 2 linkage disequilibrium groups at higher risk to CaP-specific death (OR = 1.98, p = 0.00015 and OR = 2.51, p = 0.0027). Conclusions: Risk SNPs in FHIT were implicated for aggressive disease and CaP specific death. Replication of these SNPs in other populations is warranted.