Inherited NBN Mutations and Prostate Cancer Risk and Survival

Purpose To establish the contribution of four founder alleles of NBN to prostate cancer risk and cancer survival. Materials and Methods 5189 men with prostate cancer and 6152 controls were genotyped for four recurrent variants of NBN (657del5, R215W, I171V, E185Q). Results The NBN 657del5 mutation was detected in 74 of 5189 unselected cases and in 35 of 6152 controls (OR = 2.5; p<0.0001). In carriers of 657del5 deletion, the cancer risk was restricted to men with the GG genotype of the E185Q variant of the same gene. Among men with the GG genotype, the OR associated with 657del5 was 4.4 (95%CI: 2.4 to 8.0). Among men with other E185Q genotypes, the OR associated with 657del5 was 1.4 (95% CI 0.8 to 2.4) and the interaction was significant (homogeneity p = 0.006). After a median follow-up of 109 months, mortality was worse for 657del5 mutation carriers than for non-carriers (HR=1.6; p=0.001). The adverse effect of 657del5 on survival was only seen on the background of the GG genotype of E185Q (HR=1.9, p=0.0004). Conclusion The NBN 657del5 mutation predisposes to poor prognosis prostate cancer. The pathogenicity of this mutation, with regards to both prostate cancer risk and survival, is modified by a missense variant of the same gene (E185Q).

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