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

Publication ,  Journal Article
Morton, LM; Sampson, JN; Armstrong, GT; Chen, T-H; Hudson, MM; Karlins, E; Dagnall, CL; Li, SA; Wilson, CL; Srivastava, DK; Liu, W; Kang, G ...
Published in: J Natl Cancer Inst
November 1, 2017

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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Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

November 1, 2017

Volume

109

Issue

11

Location

United States

Related Subject Headings

  • raf Kinases
  • Young Adult
  • Tumor Suppressor Proteins
  • Survivors
  • Ribosomal Protein S6 Kinases
  • Retrospective Studies
  • Radiotherapy Dosage
  • Proportional Hazards Models
  • Oncology & Carcinogenesis
  • Neoplasms, Second Primary
 

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Morton, L. M., Sampson, J. N., Armstrong, G. T., Chen, T.-H., Hudson, M. M., Karlins, E., … Robison, L. L. (2017). Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer. J Natl Cancer Inst, 109(11). https://doi.org/10.1093/jnci/djx058
Morton, Lindsay M., Joshua N. Sampson, Gregory T. Armstrong, Ting-Huei Chen, Melissa M. Hudson, Eric Karlins, Casey L. Dagnall, et al. “Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.J Natl Cancer Inst 109, no. 11 (November 1, 2017). https://doi.org/10.1093/jnci/djx058.
Morton LM, Sampson JN, Armstrong GT, Chen T-H, Hudson MM, Karlins E, et al. Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer. J Natl Cancer Inst. 2017 Nov 1;109(11).
Morton, Lindsay M., et al. “Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.J Natl Cancer Inst, vol. 109, no. 11, Nov. 2017. Pubmed, doi:10.1093/jnci/djx058.
Morton LM, Sampson JN, Armstrong GT, Chen T-H, Hudson MM, Karlins E, Dagnall CL, Li SA, Wilson CL, Srivastava DK, Liu W, Kang G, Oeffinger KC, Henderson TO, Moskowitz CS, Gibson TM, Merino DM, Wong JR, Hammond S, Neglia JP, Turcotte LM, Miller J, Bowen L, Wheeler WA, Leisenring WM, Whitton JA, Burdette L, Chung C, Hicks BD, Jones K, Machiela MJ, Vogt A, Wang Z, Yeager M, Neale G, Lear M, Strong LC, Yasui Y, Stovall M, Weathers RE, Smith SA, Howell R, Davies SM, Radloff GA, Onel K, Berrington de González A, Inskip PD, Rajaraman P, Fraumeni JF, Bhatia S, Chanock SJ, Tucker MA, Robison LL. Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer. J Natl Cancer Inst. 2017 Nov 1;109(11).
Journal cover image

Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

November 1, 2017

Volume

109

Issue

11

Location

United States

Related Subject Headings

  • raf Kinases
  • Young Adult
  • Tumor Suppressor Proteins
  • Survivors
  • Ribosomal Protein S6 Kinases
  • Retrospective Studies
  • Radiotherapy Dosage
  • Proportional Hazards Models
  • Oncology & Carcinogenesis
  • Neoplasms, Second Primary