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Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer. | LitMetric

Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.

J Natl Cancer Inst

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; Department of Epidemiology and Cancer Control, Division of Cancer Survivorship, Department of Oncology, Department of Biostatistics, Hartwell Center for Bioinformatics and Biotechnology, and Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN; Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD; Departments of Medicine, Pediatrics, and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY; Section of Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, University of Chicago, Chicago, IL; Nationwide Children's Hospital and the Ohio State University School of Medicine, Columbus, OH; Department of Pediatrics, University of Minnesota, Minneapolis, MN; Information Management Services, Inc., Calverton, MD; Cancer Prevention and Clinical Statistics Programs and Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Genetics and Department of Radiation Physics, The University of Texas at MD Anderson Cancer Center, Houston, TX; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL.

Published: November 2017

AI Article Synopsis

  • Childhood cancer survivors who underwent chest-directed radiotherapy have a significantly increased risk of developing breast cancer, but there's been limited research on genetic factors influencing this risk.
  • The study analyzed genetic data from two cohorts of female survivors, including 207 who developed breast cancer and 2,774 who did not, finding notable associations with specific genetic variants, particularly in those who received higher doses of radiation (≥10 gray).
  • Results highlighted a significant genetic locus (1q41) linked to breast cancer risk for survivors with higher radiation exposure, along with additional rare variants showing potential associations, emphasizing the need for further research into genetic predispositions in this population.

Article Abstract

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 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.

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 ] = 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.

Conclusions: 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059172PMC
http://dx.doi.org/10.1093/jnci/djx058DOI Listing

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