Subsequent neoplasm risk associated with rare variants in DNA damage response and clinical radiation sensitivity syndrome genes in the childhood cancer survivor study

Lindsay M. Morton, Danielle M. Karyadi, Stephen W. Hartley, Megan N. Frone, Joshua N. Sampson, Rebecca M. Howell, Joseph P. Neglia, Michael A. Arnold, Belynda D. Hicks, Kristine Jones, Bin Zhu, Casey L. Dagnall, Eric Karlins, Meredith S. Yeager, Wendy M. Leisenring, Yutaka Yasui, Lucie M. Turcotte, Susan A. Smith, Rita E. Weathers, Jeremy MillerByron S. Sigel, Diana M. Merino, Amy Berrington de Gonzalez, Smita Bhatia, Leslie L. Robison, Margaret A. Tucker, Gregory T. Armstrong, Stephen J. Chanock

Research output: Contribution to journalArticlepeer-review


PURPOSE: Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown.

PATIENTS AND METHODS: We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based P values using a Bonferroni-corrected significance threshold of P < 8.06 × 10 -5.

RESULTS: Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; P = 4.79 × 10 -5), most notably but nonsignificantly for FANCM (patient cases, 4.0%; matched controls, 0.6%; P = 9.64 × 10 -5). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; P = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with EXO1 variants (patient cases, 1.8%; controls, 0.4%; P = 3.31 × 10 -5), another gene implicated in DNA double-strand break repair.

CONCLUSION: In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.

Original languageEnglish (US)
Pages (from-to)926-936
Number of pages11
JournalJCO Precision Oncology
StatePublished - 2020

Bibliographical note

Funding Information:
Supported by the Intramural Program of the National Cancer Institute (NCI), National Institutes of Health (NIH); NCI Grant No. CA55727; and St Jude Children’s Research Hospital through NCI Cancer Center Support Grant No. CA21765 and the American Lebanese-Syrian Associated Charities. This work used the computational resources of the NIH High Performance Computing Biowulf cluster.

Publisher Copyright:
© 2020 by American Society of Clinical Oncology

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