Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer (original) (raw)
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Genes, Chromosomes and Cancer, 2008
As enhanced chromosomal radiosensitivity (CRS) results from non-or misrepaired double strand breaks (DSBs) and is a hallmark for breast cancer and single nucleotide polymorphisms (SNPs) in DSB repair genes, such as non homologous end-joining (NHEJ) genes, could be involved in CRS and genetic predisposition to breast cancer. In this study, we investigated the association of five SNPs in three different NHEJ genes with breast cancer in a population-based case-control setting. The total patient population composed of a selected group of patients with a family history of the disease and an unselected group, consisting mainly of sporadic cases. SNP analysis showed that the c.2099-2408G>A SNP (XRCC6) has a significant, positive odds ratio (OR) of 2.81 (95% confidence interval (CI): 1.30-6.05) for the heterozygous (He) and homozygous variant (HV) genotypes in the selected patient group. For the c.-1310 C>G SNP (XRCC5) a significant OR of 1.85 (95%CI: 1.01-3.41) was found for the He genotype in the unselected patient group. On the contrary, the HV genotype of c.1781G>T (XRCC5) displays a significant, negative OR of 0.43 (95%CI: 0.18-0.99) in the total patient population. The He1HV genotypes of the c.2099-2408G>A SNP (XRCC6) also showed high and significant ORs in the group of ''radiosensitive,'' familial breast cancer patients. In conclusion, our results provide preliminary evidence that the variant allele of c.-1310C>G (XRCC5) and c.2099-2408G>A (XRCC6) are risk alleles for breast cancer as well as CRS. The HV genotype of c.1781G>T (XRCC5) on the contrary, seems to protect against breast cancer and ionizing radiation induced micronuclei.
Nature genetics, 2009
We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P ¼ 6.74 Â 10 À10 adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P ¼ 1.74 Â 10 À7 ) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.
2011
A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r 2 5 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI 5 1.10 -1.16 and, for ER-negative tumors, OR was 1.03, 95% CI 5 0.98-1.07, case-only P-heterogeneity 5 7.6 3 10 25 ]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P 5 6.7 3 10 23 ) and lobular histology (case-only P 5 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.
Molecular Medicine Reports, 2011
Enhanced in vitro chromosomal radiosensitivity (CRS) has been proposed as a marker for low-penetrance gene mutations predisposing to breast cancer (BC). Since the double strand break (DSB) is the most detrimental form of DNA damage induced by ionizing radiation, it is possible that mutations in genes encoding proteins involved in DSB repair affect breast cancer risk. The purpose of the present study (SNPs) in Rad51 and Xrcc3 (rs1801320, rs1801321, rs1799796, rs861539 and rs1799794) exhibited an association with breast cancer susceptibility in a Belgian population of BC patients with a known or putative genetic predisposition. We also ascertained whether a relationship exists between the occurrence of the 'variant' alleles of these variations and in vitro CRS. Blood samples were obtained from BC patients and from healthy female individuals. Variations in the 5' UTR of Rad51 and Xrcc3 were genotyped, and statistical analysis was performed. The results showed that low-penetrant variations in Rad51 and Xrcc3, two proteins belonging to the homologous recombination DSB repair pathway, may modify BC risk in patients already carrying a pathological mutation in the highly penetrant BC genes BRCA1 and BRCA2. Combined risk genotype analysis revealed that Rad51 SNPs enhance BC risk in BRCA2 patients, whereas Xrcc3 BC risk in carriers of BRCA1 mutations and in patients with hereditary BC. When four putative risk genotypes of Rad51 and Xrcc3 were combined, positive significant odds ratios were obtained in the entire patient population and in patients with a hereditary history of disease. Although obtained from a limited number of patients, our data are supportive of a polygenic model whereby combinations of weak variations are responsible for an enhanced BC risk by acting jointly with high-penetrant mutations in BRCA1 or BRCA2.
Human Mutation, 2012
Ionizing radiation (IR) is a breast carcinogen that induces DNA double-strand breaks (DSBs), and variation in genes involved in the DNA DSB response has been implicated in radiation-induced breast cancer. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) study is a populationbased study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location-specific radiation dose received by the contralateral breast was estimated from radiotherapy records and mathematical models. One hundred fifty-two SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1) involved in the DNA DSBs response were genotyped. No variants or haplotypes were associated with CBC risk (649 cases and 1,284 controls) and no variants were found to interact with radiation dose. Carriers of a RAD50 haplotype exposed to ≥1 gray (Gy) had an increased risk of CBC compared with unexposed carriers (Rate ratios [RR] = 4.31 [95% confidence intervals [CI] 1.93-9.62]); with an excess relative risk (ERR) per Gy = 2.13 [95% CI 0.61-5.33]). Although the results of this study were largely null, carriers of a haplotype in RAD50 treated with radiation had a greater CBC risk than unexposed carriers. This suggests that carriers of this
Http Dx Doi Org 10 1667 Rr1985 1, 2010
As genome-wide association studies of breast cancer are replicating findings and refinement studies are narrowing the signal location, additional efforts are necessary to elucidate the underlying functional relationships. One approach is to evaluate variation in risk by genotype based on known breast carcinogens, such as ionizing radiation. Given the public health concerns associated with recent increases in medical radiation exposure, this approach may also identify potentially susceptible sub-populations. We examined interaction between 27 newly identified breast cancer risk alleles (identified within the NCI Cancer Genetic Markers of Susceptibility and the Breast Cancer Association Consortium genome-wide association studies) and occupational and medical diagnostic radiation exposure among 859 cases and 1083 controls nested within the United States Radiologic Technologists cohort. We did not find significant variation in the radiation-related breast cancer risk for the variant in RAD51L1 (rs10483813) on 14q24.1 as we had hypothesized. In exploratory analyses, we found that the radiation-associated breast cancer risk varied significantly by linked markers in 5p12 (rs930395, rs10941679, rs2067980, and rs4415084) in the mitochondrial ribosomal protein S30 (MRPS30) gene (p interaction =0.04). Chance, however, may explain these findings, and as such, these results need to be confirmed in other populations with low to moderate levels of radiation exposure. Even though a complete
International Journal of Radiation Oncology*Biology*Physics, 2007
Purpose: To identify haplotypes of single nucleotide polymorphism markers associated with the risk of early adverse skin reactions (EASRs) after radiotherapy in breast cancer patients. Methods and Materials: DNA was sampled from 399 Japanese breast cancer patients who qualified for breast-conserving radiotherapy. Using the National Cancer Institute-Common Toxicity Criteria scoring system, version 2, the patients were grouped according to EASRs, defined as those occurring within 3 months of starting radiotherapy (Grade 1 or less, n = 290; Grade 2 or greater, n = 109). A total of 999 single nucleotide polymorphisms from 137 candidate genes for radiation susceptibility were genotyped, and the haplotype associations between groups were assessed. Results: The global haplotype association analysis (p < 0.05 and false discovery rate < 0.05) indicated that estimated haplotypes in six loci were associated with EASR risk. A comparison of the risk haplotype with the most frequent haplotype in each locus showed haplotype GGTT in CD44 (odds ratio [OR] = 2.17; 95% confidence interval [CI], 1.07-4.43) resulted in a significantly greater EASR risk. Five haplotypes, CG in MAD2L2 (OR = 0.55; 95% CI, 0.35-0.87), GTTG in PTTG1 (OR = 0.48; 95% CI, 0.24-0.96), TCC (OR = 0.48; 95% CI, 0.26-0.89) and CCG (OR = 0.50; 95% CI, 0.27-0.92) in RAD9A, and GCT in LIG3 (OR = 0.46; 95% CI, 0.22-0.93) were associated with a reduced EASR risk. No significant risk haplotype was observed in REV3L. Conclusion: Individual radiosensitivity can be partly determined by these haplotypes in multiple loci. Our findings may lead to a better understanding of the mechanisms underlying the genetic variation in radiation sensitivity and resistance among breast cancer patients. Ó 2007 Elsevier Inc.
International Journal of Cancer, 2008
High-dose ionizing radiation exposure to the breast and rare autosomal dominant genes have been linked with increased breast cancer risk, but the role of low-to-moderate doses from protracted radiation exposure in breast cancer risk and its potential modification by polymorphisms in DNA repair genes has not been previously investigated among large numbers of radiation-exposed women with detailed exposure data. Using carefully reconstructed estimates of cumulative breast doses from occupational and personal diagnostic ionizing radiation, we investigated the potential modification of radiation-related breast cancer risk by 55 candidate single nucleotide polymorphisms in 17 genes involved in base excision or DNA double-strand break repair among 859 cases and 1083 controls from the United States Radiologic Technologists (USRT) cohort. In multivariable analyses, WRN V114I (rs2230009) significantly modified the association between cumulative occupational breast dose and risk of breast cancer (adjusted for personal diagnostic exposure) (p = 0.04) and BRCA1 D652N (rs4986850), PRKDC IVS15 + 6C > T (rs1231202), PRKDC IVS34 + 39T > C (rs8178097) and PRKDC IVS31 − 634C > A (rs10109984) significantly altered the personal diagnostic radiation exposure-response relationship (adjusted for occupational dose) (p ≤ 0.05). None of the remaining 50 SNPs significantly modified breast cancer radiation dose-response relationships. The USRT genetic study provided a unique opportunity to examine the joint effects of common genetic variation and ionizing radiation exposure on breast cancer risk using detailed occupational and personal diagnostic exposure data. The suggestive evidence found for modification of radiation-related breast cancer risk for 5 of the 55 SNPs evaluated requires confirmation in larger studies of women with quantified radiation breast doses in the low-to-moderate range. © 2007 Wiley-Liss, Inc.