Novel Breast Cancer Risk Alleles and Interaction with Ionizing Radiation among U.S. Radiologic Technologists (original) (raw)
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Cancer Epidemiology Biomarkers & Prevention, 2008
Genome-wide association studies are discovering relationships between single-nucleotide polymorphisms and breast cancer, but the functions of these singlenucleotide polymorphisms are unknown and environmental exposures are likely to be important. We assessed whether breast cancer risk single-nucleotide polymorphisms interacted with ionizing radiation, a known breast carcinogen, among 859 cases and 1,083 controls nested in the U.S. Radiologic Technologists cohort. Among 11 Breast Cancer Association Consortium risk single-nucleotide polymorphisms, we found that the genotype-associated breast cancer risk varied significantly by radiation dose for rs2107425 in the H19 gene (P interaction = 0.001). H19 is a maternally expressed imprinted mRNA that is closely involved in regulating the IGF2 gene and could exert its influence by this or by some other radiation-related pathway.
Cancer Epidemiology Biomarkers & Prevention, 2007
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.
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.
Breast Cancer Research and Treatment, 2009
Ionizing radiation-associated breast cancer risk appears to be modified by timing of reproductive events such as age at radiation exposure, parity, age at first live birth, and age at menopause. However, potential breast cancer risk modification of low-to moderate radiation dose by polymorphic estrogen metabolism-related gene variants has not been routinely investigated. We assessed breast cancer risk of 12 candidate variants in 12 genes involved in steroid metabolism, catabolism, binding, or receptor functions in a study of 859 cases and 1083 controls within the US Radiologic Technologists (USRT) cohort. Using cumulative breast dose estimates from a detailed assessment of occupational and personal diagnostic ionizing radiation exposure, we investigated the joint effects of genotype on the risk of breast cancer. In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the CYP3A4 M445T minor allele (rs4986910, OR=0.3; 95% CI 0.1-0.9). We found a borderline increased breast cancer risk with having both minor alleles of CYP1B1 V432L (rs1056836, CC vs. GG, OR=1.2; 95% CI 0.9-1.6). Assuming a recessive model, the minor allele of CYP1B1 V432L significantly increased the doseresponse relationship between personal diagnostic x-ray exposure and breast cancer risk, adjusted for cumulative occupational radiation dose (p interaction =0.03) and had a similar joint effect for cumulative occupational radiation dose adjusted for personal diagnostic x-ray exposure (p interaction =0.06). We found suggestive evidence that common variants in selected estrogen metabolizing genes may modify the association between ionizing radiation exposure and breast cancer risk.
International Journal of Cancer, 2008
Exposure to ionizing radiation has been consistently associated with increased risk of female breast cancer. Although the majority of DNA damage caused by ionizing radiation is corrected by the base-excision repair pathway, certain types of multiple-base damage can only be repaired through the nucleotide excision repair pathway. In a nested case-control study of breast cancer in US radiologic technologists exposed to low levels of ionizing radiation (858 cases, 1,083 controls), we examined whether risk of breast cancer conferred by radiation was modified by nucleotide excision gene polymorphisms ERCC2 (XPD) rs13181, ERCC4 (XPF) rs1800067 and rs1800124, ERCC5 (XPG) rs1047769 and rs17655; and ERCC6 rs2228526. Of the 6 ERCC variants examined, only ERCC5 rs17655 showed a borderline main effect association with breast cancer risk (OR GC 5 1.1, OR CC 5 1.3; p-trend 5 0.08), with some indication that individuals carrying the C allele variant were more susceptible to the effects of occupational radiation (EOR/Gy GG 5 1.0, 95% CI 5 <0, 6.0; EOR/Gy GC/CC 5 5.9, 95% CI 5 0.9, 14.4; p het 5 0.10). ERCC2 rs13181, although not associated with breast cancer risk overall, statistically significantly modified the effect of occupational radiation dose on risk of breast cancer (EOR/Gy AA 5 9.1, 95% CI 5 2.1221.3; EOR/Gy AC/CC 5 0.6, 95% CI 5 <0, 4.6; p het 5 0.01). These results suggest that common variants in nucleotide excision repair genes may modify the association between occupational radiation exposure and breast cancer risk.
JNCI: Journal of the National Cancer Institute
Background: Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking. Methods: We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 highquality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided. Results: Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1, risk allele frequency in control subjects [RAF controls ] ¼ 0.46, hazard ratio ¼ 1.92, 95% confidence interval ¼ 1.49 to 2.44, P ¼ 7.09 Â 10-9). Two rare variants also showed potentially promising associations (breast radiation !10 gray: rs74949440, 11q23, TAGLN, RAF controls ¼ 0.02, P ¼ 5.84 Â 10-8 ; <10 gray: ARTICLE
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
Identification of women with an increased risk of developing radiation-induced breast cancer
Breast Cancer Research, 2007
In the previous issue of Breast Cancer Research, Broeks and collaborators present the results of a study suggesting that germline mutations in BRCA1, BRCA2, ATM or CHEK2 may double the risk of radiation-induced contralateral breast cancer following radiotherapy for a first breast cancer. The assocation appeared to be strongest among women who were below the age of 40 at the time of their first breast cancer and among women who developed their second cancer 5 years or more after the first. While there were a number of methodological issues that might limit the conclusions drawn from this paper, this is one of several recent studies suggesting that carriers of pathogenic alleles in DNA repair and damage recognition genes may have an increased risk of breast cancer following exposure to ionising radiation, even at low doses. This finding has important implications for the protection of breast cancer patients and their close relatives. If confirmed, mutation carriers may wish to consider alternatives to Xray for diagnostic purposes. The need for tailored cancer treatment strategies in carriers should also be evaluated carefully.
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.