Morton Lindsay M, Karyadi Danielle M, Hartley Stephen W, Frone Megan N, Sampson Joshua N, Howell Rebecca M, Neglia Joseph P, Arnold Michael A, Hicks Belynda D, Jones Kristine, Zhu Bin, Dagnall Casey L, Karlins Eric, Yeager Meredith S, Leisenring Wendy M, Yasui Yutaka, Turcotte Lucie M, Smith Susan A, Weathers Rita E, Miller Jeremy, Sigel Byron S, Merino Diana M, Berrington de Gonzalez Amy, Bhatia Smita, Robison Leslie L, Tucker Margaret A, Armstrong Gregory T, Chanock Stephen J
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, TX.
JCO Precis Oncol. 2020 Aug 21;4. doi: 10.1200/PO.20.00141. eCollection 2020.
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 values using a Bonferroni-corrected significance threshold of < 8.06 × 10.
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; = 4.79 × 10), most notably but nonsignificantly for (patient cases, 4.0%; matched controls, 0.6%; = 9.64 × 10). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with variants (patient cases, 1.8%; controls, 0.4%; = 3.31 × 10), another gene implicated in DNA double-strand break repair.
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.
儿童癌症放疗与后续肿瘤（SN）风险升高相关，但DNA损伤反应和辐射敏感性基因中的罕见变异对SN风险的影响尚不清楚。
我们对一组1970年至1986年期间首次诊断的儿童癌症幸存者进行了全外显子组测序（平均随访32.7年），并根据放疗记录重建身体各部位的剂量。我们确定了发生先前报道与放疗相关的SN类型（放疗相关SN；如基底细胞癌[BCC]、乳腺癌、脑膜瘤、甲状腺癌、肉瘤）的患者以及匹配的对照组（性别、儿童癌症类型/诊断、年龄、SN位置、辐射剂量、生存情况）。条件逻辑回归评估了476个DNA损伤反应或辐射敏感性基因中与潜在蛋白质损伤罕见变异（SnpEff、ClinVar）相关的SN风险，使用基于精确排列的P值，并采用Bonferroni校正的显著性阈值P<8.06×10⁻⁵。
在5105名欧洲血统的儿童癌症幸存者中，1108名（21.7%）发生了至少1例放疗相关SN。排除BCC后，野外放疗相关SN风险与同源重组修复（HRR）基因变异相关（患者病例组为23.2%；对照组为10.8%；比值比[OR]为2.6；95%置信区间为1.7至3.9；P = 4.79×10⁻³），最显著的是BRCA2（患者病例组为4.0%；匹配对照组为0.6%；P = 9.64×10⁻³），但不具有统计学意义。排除BCC后，HRR变异与可能的近场/场内放疗相关SN无关（患者病例组为12.7%；匹配对照组为12.9%；P = 0.92）。无论辐射剂量如何，放疗相关SN风险也与RAD51变异相关（患者病例组为1.8%；对照组为0.4%；P = 3.31×10⁻²），RAD51是另一个与DNA双链断裂修复有关的基因。
在这项大规模发现研究中，我们确定了儿童癌症后放疗相关SN风险与参与DNA双链断裂修复的基因中潜在蛋白质损伤罕见变异之间的新关联，特别是HRR。通过重复验证，这些结果可能会影响儿童癌症幸存者的筛查建议以及治疗方法的风险效益评估。
