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

Abstract

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.

FIG 1.

Selected characteristics of childhood cancer survivors of European descent with high-quality whole-exome sequencing data. AML, acute myeloid leukemia; BCC, basal cell carcinoma; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma; SN, subsequent neoplasm; RT-SN, radiotherapy-related subsequent neoplasm. (*) If dose to body region in which SN was observed was ≥ 10 Gy, SN was categorized as likely in/near field. Conversely, if dose was < 10 Gy, SN was categorized as likely out of field. For patient cases who developed multiple RT-SNs (Data Supplement), (continued on following page) radiation dose was estimated to first RT-SN type that occurred. For analyses of RT-SNs excluding BCC, radiation dose was estimated to first non-BCC RT-SN type. (†) Vast majority of SNs were invasive malignancies (n = 900; 81.2%), with the remainder being ductal carcinomas in situ (n = 45), meningiomas of benign (n = 116) or uncertain behavior (n = 13), other CNS tumors of uncertain behavior (n = 5), soft tissue sarcomas of benign (n = 19) or uncertain behavior (n = 2), other in situ RT-SN types (n = 4), or other RT-SN types of benign (n = 1) or uncertain behavior (n = 3). (‡) Other CNS types included glioma (n = 20), medulloblastoma/primitive neuroectodermal tumor (n = 3), and poorly specified (n = 6). Other RT-SN types included cancers of colon/rectum (n = 26), other GI organs (n = 13), parotid (n = 14), lung (n = 11), head/neck (n = 9), and bladder (n = 8). (∼) Data are not applicable to the matched controls.

FIG 2.

Radiation sensitivity syndromes and DNA damage response pathways^- considered in this analysis (Data Supplement provides additional details and specific genes).

FIG 3.

Distributions of (A) radiotherapy-related subsequent neoplasm (RT-SN) type (excluding basal cell carcinoma [BCC]) and location, (B) type of first primary childhood cancer, (C) age at RT-SN diagnosis, (D) time from childhood cancer diagnosis to RT-SN, and (E) vital status at the end of follow-up by carrier status of potentially protein-damaging homologous recombination repair (HRR) gene variants. HR, hazard ratio; NHL, non-Hodgkin lymphoma.