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- Title
Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.
- Authors
Morton, Lindsay M.; Sampson, Joshua N.; Armstrong, Gregory T.; Ting-Huei Chen; Hudson, Melissa M.; Karlins, Eric; Dagnall, Casey L.; Li, Shengchao Alfred; Wilson, Carmen L.; Srivastava, Deo Kumar; Wei Liu; Kang, Guolian; Oeffinger, Kevin C.; Henderson, Tara O.; Moskowitz, Chaya S.; Gibson, Todd M.; Merino, Diana M.; Bhatia, Smita; Chanock, Stephen J.; Tucker, Margaret A.
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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 high-quality 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.<bold>Results: </bold>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 ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts.<bold>Conclusions: </bold>Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer.
- Subjects
BREAST cancer risk factors; LOCUS in human genetics; GENETICS of breast cancer; RADIOTHERAPY complications; BREAST cancer patients; BREAST; BREAST tumors; COMPARATIVE studies; DISEASE susceptibility; HODGKIN'S disease; LEUKEMIA; LONGITUDINAL method; RESEARCH methodology; MEDICAL cooperation; MICROFILAMENT proteins; MUSCLE proteins; PROTEINS; RADIATION doses; RADIATION carcinogenesis; RESEARCH; RESEARCH funding; TRANSFERASES; EVALUATION research; PROPORTIONAL hazards models; RETROSPECTIVE studies; SECONDARY primary cancer; SEQUENCE analysis
- Publication
JNCI: Journal of the National Cancer Institute, 2017, Vol 109, Issue 11, p1
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djx058