ABSTRACT:Recently, the SNPs rs11614913 in hsa-mir-196a2 and rs3746444 in hsa-mir-499 were reported to be associated with increased breast cancer risk, and the SNP rs2910164 in hsa-mir146a was shown to have an effect on age of breast cancer diagnosis. In order to further investigate the effect of these SNPs, we genotyped a total of 1894 breast cancer cases negative for diseasecausing mutations or unclassified variants in BRCA1 and BRCA2, and 2760 controls from Germany and Italy. We compared the genotype and allele frequencies of rs2910164, rs11614913 and rs3746444 in cases versus controls of the German and Italian series, and of the two series combined; we also investigated the effect of the three SNPs on age at breast cancer diagnosis. None of the performed analyses showed statistically significant results. In conclusion, our data suggested lack of association between SNPs rs2910164, rs11614913 and rs3746444 and breast cancer risk, or age at breast cancer onset.

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In our study, we analysed two SNPs, rs4636297 within miR-126 and rs41272366 within miR-335, in three study populations for a putative association with breast cancer risk. We compared the genotype and allele frequencies of rs4636297and rs41272366 in 2854 cases versus 3188 controls of the three study populations independently and combined. None of the performed analyses showed statistically significant results. In conclusion, our data suggest that the two genetic variants within miR-126 and miR-335 are not associated with breast cancer risk.

Dysregulation of apoptosis plays an important role in carcinogenesis. Therefore, apoptosis-associated genes like the death receptor 4 (DR4, TRAIL-R1) are interesting candidates for modifying the penetrance of breast and ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The DR-4 haplotype 626C-683C [626C>G, Thr209Arg (rs4871857) and 683A>C, Glu228Ala (rs17088993)] has recently been linked to an increased risk of breast cancer. To evaluate whether DR4 626C>G or DR4 683A>C modifies the risk of breast or ovarian cancer in carriers of BRCA1 and BRCA2 mutations, 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 of DR4 683A>C with a higher risk for ovarian cancer in carriers of BRCA1 mutations [n 5 557, hazard ratio 1.78 (1.24-2.55), p 5 0.009]. Our results thus indicate that the DR4 683A>C variant modifies the risk of ovarian cancer in carriers of BRCA1 mutations.The transmembrane death receptors are members of the tumor necrosis factor (TNF) superfamily, characterized by their similar, cysteine-rich extracellular domains. 1 These receptors are involved in apoptosis, the programmed cell death, which keeps cell numbers and tissue sizes constant and is a critically important process during carcinogenesis. 2 As inactivation of the death receptors is expected to result in deficient apoptotic signaling 3 and thus in tumor growth, they are considered to be excellent candidate tumor suppressor genes.The TNF-related apoptosis-inducing ligand (TRAIL) binds to the proapoptotic death receptor 4 (DR4, TNFRSF10A, TRAIL-R1). 2 The DR4 gene is located on chromosome 8p21-22 and encodes 486 amino acids. It forms two extracellular cysteine-rich, ligand-binding pseudorepeats (50s and 90s loops), a single transmembrane helix and a cytoplasmatic death domain that is able to engage the suicide machinery of cells and activate the apoptotic proteases to mediate apoptosis within a matter of hours. [4][5][6] It has been shown recently, that single amino acid mutations in wild-type TRAIL significantly changes the affinity of TRAIL toward its death receptor. 7 As both the single nucleotide polymorphisms (SNPs) analyzed within our study reside next to the DR4 ligand binding