Association ofdeath receptor 4variant (683A>C) with ovarian cancer risk inBRCA1mutation carriers

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Dysregulation of apoptosis plays an important role in carcinogenesis. Therefore, apoptosis-associated genes like thedeath receptor 4(DR4, TRAIL-R1) are interesting candidates for modifying the penetrance of breast and ovarian cancer in carriers ofBRCA1andBRCA2mutations. TheDR-4haplotype 626C–683C [626C>G, Thr209Arg (rs4871857) and 683A>C, Glu228Ala (rs17088993)] has recently been linked to an increased risk of breast cancer. To evaluate whetherDR4626C>G orDR4683A>C modifies the risk of breast or ovarian cancer in carriers ofBRCA1andBRCA2mutations, we undertook a national multicenter study including data of 840 carriers of breast cancer gene (BRCA) mutations. DNA samples were collected from 12 German research centers between 1996 and 2005 and were genotyped by the Taqman allelic discrimination assay. The association between genotypes and incidence of breast or ovarian cancer data was evaluated using a Cox proportional hazards regression model. We found evidence for a significant association ofDR4683A>C with a higher risk for ovarian cancer in carriers ofBRCA1mutations [n= 557, hazard ratio 1.78 (1.24–2.55),p= 0.009]. Our results thus indicate that theDR4683A>C variant modifies the risk of ovarian cancer in carriers of BRCA1 mutations.

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