Variants in activators and downstream targets of ATM, radiation exposure, and contralateral breast cancer risk in the WECARE study

Abstract

Ionizing radiation 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 population-based study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location-specific radiation dose received to the contralateral breast was estimated from radiotherapy records and mathematical models. 152 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, 1284 controls) and no variants were found to interact with radiation dose. Carriers of a RAD50 haplotype exposed to ≥1Gy had an increased risk of CBC compared with unexposed carriers (RR=4.31 (95% CI 1.93-9.62)); with an excess relative risk (ERR)/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 haplotype may be susceptible to the DNA-damaging effects of radiation therapy associated with radiation-induced breast cancer.

Variation in Genes Related to Obesity, Weight, and Weight Change and Risk of Contralateral Breast Cancer in the WECARE Study Population

“…Recruitment, eligibility criteria, data and biospecimen collection, and genotype methods have been described (2, 4). …”

“…Twelve candidate genes were selected based on biological plausibility and known involvement with adipose tissue metabolism and obesity ( LEP , LEPR , ADIPOQ , ADIPOR1 , ADIPOR2 , HIF1A , PLAU , PLAUR , SERPINE1, IGF2BP1 ) (3) or a functional relationship with both obesity and DNA repair ( IRS2 , FOXO1 ) (8). SNPs identified from GWAS were genotyped directly, whereas SNPs in candidate genes were selected using a tagSNP approach, supplemented with potentially functionally relevant SNPs from dbSNP (4). A total of 194 SNPs in 20 genes was genotyped.…”

A Newfound Association between MDC1 Functional Polymorphism and Lung Cancer Risk in Chinese

“…An Chinese study reported a variant allele of MDC1 exhibited a significant association with EBV seropositivity [28]. A Caucasian study reported no variant of MDC1 was associated with breast cancer risk as well as DNA-damaging effects of radiation therapy [47]. However, the above studies were all lack of study power because of their limited sample sizes.…”

Breast Cancer Biology for the Radiation Oncologist

“…Brooks et al (2012) examined 152 SNPs from six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, and TP53BP1) were genotyped in the WECARE cohort to see if any of them conferred a higher risk for CBC. The MRN complex or MRE11-RAD50-NSB1 complex is part of the BRCA1 associated genome surveillance complex.…”