BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC.

Little is known about the etiologic profile of triple-negative breast cancer (TNBC; ER-/PR-/HER2-), a breast cancer subtype associated with high mortality and inadequate therapeutic options. We undertook the study to assess the risk of TNBC among women 45 years of age and younger in relation to demographic/lifestyle factors, reproductive history, and oral contraceptive (OC) use. Study participants were ascertained in two prior population-based, case-control studies. Eligible cases included all primary invasive breast cancers among women ages 20-45 in the Seattle-Puget Sound area, diagnosed between January 1983 and December 1992 for whom complete data was obtained for ER, PR and HER2 status (n=897; including n=187 TNBC cases). Controls were age matched and ascertained via random digit dialing. OC use ≥1 year was associated with a 2.5-fold increased risk of TNBC (95% CI 1.4-4.3) and no significantly increased risk of non-TNBC (P heterogeneity .008). Further, the risk among OC users conferred by longer OC duration and by more recent use was significantly greater for TNBC than non-TNBC (P heterogeneity .02 and .01, respectively). Among women ≤40 years, the relative risk of TNBC associated with OC use ≥1 year was 4.2 (95% CI 1.9-9.3), whereas there was no significantly increased risk with OC use for non-TNBC among women ≤40 years, nor for TNBC or non-TNBC among women 41-45 years of age. In conclusion, significant heterogeneity exists for the association of OC use and breast cancer risk between TNBC and non-TNBC among young women, lending support to a distinct etiology.

Genetic and environmental factors contribute to the etiology of neural tube defects (NTDs). While periconceptional folic acid supplementation is known to significantly reduce the risk of NTDs, folate metabolic pathway related factors do not account for all NTDs. Evidence from mouse models indicates that the tumor protein p53 (TP53) is involved in implantation and normal neural tube development. To determine whether genetic variation in the TP53 might contribute to NTD risk in humans, we constructed a high resolution linkage disequilibrium (LD) map of the TP53 genomic region based on genotyping 21 markers in an Irish population. We found that nine of these variants can be used to capture the majority of common variation in the TP53 genomic region. In contrast, the 3-marker haplotype commonly reported in the TP53 literature offers limited coverage of the variation in the gene. We used the expanded set of polymorphisms to measure the influence of TP53 on NTDs using both case-control and family-based tests of association. We also assayed a functional variant in the p53 regulator MDM2 (rs2279744). Alleles of three noncoding TP53 markers were associated with NTD risk. A case effect was seen with the GG genotype of rs1625895 in intron 6 (OR = 1.37 [1.04-1.79], p=0.02). A maternal effect was seen with the 135/135 genotype of the intron 1 VNTR (OR = 1.86 [1.16-2.96], p=0.01) and the TT genotype of rs1614984 (RR = 0.58 [0.37-0.91], p=0.02). As multiple comparisons were made, these cannot be considered definitive positive findings and additional investigation is required.