ABSTRACT
Recent genome-wide association studies have identified a breast cancer susceptibility locus on 16q12 with an unknown biological basis. We used a set of single nucleotide polymorphism (SNP) markers to generate a fine-scale map and narrowed the region of association to a 133 kb DNA segment containing the largely uncharacterized hypothetical gene LOC643714, a short intergenic region and the 5' end of TOX3. Re-sequencing this segment in European subjects identified 293 common polymorphisms, including a set of 26 highly correlated candidate causal variants. By evaluation of these SNPs in five breast cancer case-control studies involving more than 23 000 subjects from populations of European and Southeast Asian ancestry, all but 14 variants could be excluded at odds of <1:100. Most of the remaining variants lie in the intergenic region, which exhibits evolutionary conservation and open chromatin conformation, consistent with a regulatory function. African-American case-control studies exhibit a different pattern of association suggestive of an additional causative variant.
Subject(s)
Breast Neoplasms/genetics , Chromosomes, Human, Pair 16/genetics , Genetic Predisposition to Disease , Chromosome Mapping , Female , Genetic Markers , Genome-Wide Association Study , Humans , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: Although genes involved in apoptosis pathways and DNA repair pathways are both essential for maintaining genomic integrity, genetic variants in DNA repair have been thought to increase susceptibility to radiation carcinogenesis, but similar hypotheses have not generally been raised about apoptosis genes. For this reason, potential modification of the relationship between ionizing radiation exposure and breast cancer risk by polymorphic apoptosis gene variants have not been investigated among radiation-exposed women. METHODS: In a case-control study of 859 cases and 1,083 controls within the U.S. Radiologic Technologists cohort, we assessed breast cancer risk with respect to 16 candidate variants in eight genes involved in apoptosis, inflammation, and proliferation. Using carefully reconstructed cumulative breast dose estimates from occupational and personal diagnostic ionizing radiation, we also investigated the joint effects of these polymorphisms on the risk of breast cancer. RESULTS: In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the homozygous minor allele of CASP8 D302H [rs1045485, odds ratio (OR), 0.3; 95% confidence interval (95% CI), 0.1-0.8]. We found a significantly increased breast cancer risk with increasing minor alleles for IL1A A114S (rs17561); heterozygote OR 1.2 (95% CI, 1.0-1.4) and homozygote OR 1.5 (95% CI, 1.1-2.0), P(trend) = 0.008. Assuming a dominant genetic model, IL1A A114S significantly modified the dose-response relationship between cumulative personal diagnostic radiation and breast cancer risk, adjusted for occupational dose (P(interaction) = 0.004). CONCLUSION: The U.S. Radiologic Technologists breast cancer study provided a unique opportunity to examine the joint effects of common genetic variation and ionizing radiation exposure to the breast using detailed occupational and personal diagnostic dose data. We found evidence of effect modification of the radiation and breast cancer dose-response relationship that should be confirmed in studies with more cases and controls and quantified radiation breast doses in the low-to-moderate range.
Subject(s)
Apoptosis/genetics , Breast Neoplasms/genetics , Cell Division/genetics , Neoplasms, Radiation-Induced/genetics , Technology, Radiologic , Aged, 80 and over , Alleles , Animals , Apoptosis/radiation effects , CASP8 and FADD-Like Apoptosis Regulating Protein/genetics , Case-Control Studies , Cell Division/radiation effects , Cohort Studies , Dose-Response Relationship, Radiation , Female , Gene Expression/radiation effects , Heterozygote , Homozygote , Humans , Interleukin-1alpha/genetics , Middle Aged , Neoplasms, Radiation-Induced/pathology , Odds Ratio , Polymorphism, Single Nucleotide/genetics , Risk AssessmentABSTRACT
SUMMARY: BACKGROUND Over-expression of the human epidermal growth factor receptor 2 (Her2) protooncogene is associated with poor prognosis among female patients with breast cancer. A polymorphism in the HER2 gene (I655V) has been associated with an elevated risk of breast cancer in some ethnic groups. METHODS Subjects from a community-based study of 5318 Ashkenazim from the Washington, DC area were selected for analysis of the I655V HER2 germline polymorphism. We estimated age-specific breast cancer risk from HER2 I655V based on the family history data, using the female first-degree relatives of the study participants and a novel extension of the kin cohort method. RESULTS The estimated cumulative risk of breast cancer to age 70 was approximately 30% higher among HER2 I655V carriers than noncarriers (RR = 1.33; 95% confidence interval [CI] = 1.03-1.83). The effect of the allele seems stronger at younger ages (among women younger than 50 years, RR = 2.11; CI = 1.39-3.28) and especially among younger women with a family history of breast cancer (RR = 8.9; CI = 1.9-19.7). Increased risk of breast cancer associated with the I655V allele was also observed among BRCA1/2 mutation carriers, although these results are based on small numbers. CONCLUSION These analyses suggest that the HER2 valine allele might be associated with increased risk of breast cancer, especially in young women and in women with a family history of the disease.
