title: Variants in activators and downstream targets of ATM, radiation exposure, and contralateral breast cancer risk in the WECARE study.
abstract: 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 population-based 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 haplotype may be susceptible to the DNA-damaging effects of radiation therapy associated with radiation-induced breast cancer.
authors: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. brooksj@mskcc.org
authors: Jennifer D
authors: JD
authors: Brooks
authors: Sharon N
authors: SN
authors: Teraoka
authors: Anne S
authors: AS
authors: Reiner
authors: Jaya M
authors: JM
authors: Satagopan
authors: Leslie
authors: L
authors: Bernstein
authors: Duncan C
authors: DC
authors: Thomas
authors: Marinela
authors: M
authors: Capanu
authors: Marilyn
authors: M
authors: Stovall
authors: Susan A
authors: SA
authors: Smith
authors: Shan
authors: S
authors: Wei
authors: Roy E
authors: RE
authors: Shore
authors: John D
authors: JD
authors: Boice
authors: Charles F
authors: CF
authors: Lynch
authors: Lene
authors: L
authors: Mellemkjaer
authors: Kathleen E
authors: KE
authors: Malone
authors: Xiaolin
authors: X
authors: Liang
authors: Robert W
authors: RW
authors: Haile
authors: Patrick
authors: P
authors: Concannon
authors: Jonine L
authors: JL
authors: Bernstein
mesh_terms: D017766:Acid Anhydride Hydrolases; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011829:Radiation Dosage; D011878:Radiotherapy / Q000009:adverse effects; D012307:Risk Factors
chemical_list: D004268:DNA-Binding Proteins; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes