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

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  • 1Division 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.

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Genetic factors influence breast cancer risk in childhood cancer survivors exposed to chest radiotherapy. Specific gene variants modify radiation

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Area of Science:

  • Oncology
  • Genetics
  • Radiation Oncology

Background:

  • Childhood cancer survivors treated with chest radiotherapy face a significantly increased risk of developing breast cancer.
  • Genetic susceptibility to breast cancer is well-documented in the general population, but less understood in this specific survivor cohort.

Purpose of the Study:

  • To investigate genetic susceptibility to breast cancer in female survivors of childhood cancer exposed to chest radiotherapy.
  • To identify specific genetic variants associated with breast cancer risk following radiation treatment for childhood cancer.

Main Methods:

  • Conducted a genome-wide association study (GWAS) in two large cohorts of childhood cancer survivors (Childhood Cancer Survivor Study and St. Jude Lifetime Cohort).
  • Analyzed data from 207 breast cancer survivors and 2774 controls, with detailed treatment and follow-up data.
  • Utilized genotyping and imputation to analyze over 16 million genetic variants, stratifying by radiation dose ( <10 gray and ≥10 gray).

Main Results:

  • Identified a significant locus on chromosome 1q41 (rs4342822) associated with breast cancer risk in survivors who received ≥10 gray of breast radiation (Hazard Ratio = 1.92, P = 7.09×10⁻⁹).
  • Discovered two additional potentially significant variants (rs74949440 on 11q23 for ≥10 gray and rs17020562 on 1q32.3 for <10 gray radiation).
  • Findings were consistent across both survivor cohorts and specific to radiation dose subgroups.

Conclusions:

  • Germline genetic factors, beyond known high-risk syndromes, play a role in modifying breast cancer risk after childhood cancer treatment.
  • These genetic variations can influence the impact of radiation exposure on subsequent breast cancer development in survivors.
  • Highlights the importance of considering genetic predisposition in the long-term surveillance and risk management of childhood cancer survivors.