Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study.

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. 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 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; 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.

Informations de copyright

© 2020 by American Society of Clinical Oncology.

Déclaration de conflit d'intérêts

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Belynda D. HicksEmployment: United Therapeutics (I) Stock and Other Ownership Interests: United Therapeutics (I) Honoraria: Roche Molecular Diagnostics Travel, Accommodations, Expenses: Roche Molecular Diagnostics, United Therapeutics (I)Susan A. SmithHonoraria: Memorial Sloan-Kettering Cancer Center Travel, Accommodations, Expenses: Memorial Sloan-Kettering Cancer CenterDiana M. MerinoTravel, Accommodations, Expenses: Aetion No other potential conflicts of interest were reported.