Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN.
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN.
J Clin Oncol. 2020 Aug 20;38(24):2728-2740. doi: 10.1200/JCO.19.02760. Epub 2020 Jun 4.
To investigate cancer treatment plus pathogenic germline mutations (PGMs) in DNA repair genes (DRGs) for identification of childhood cancer survivors at increased risk of subsequent neoplasms (SNs).
Whole-genome sequencing was performed on blood-derived DNA from survivors in the St Jude Lifetime Cohort. PGMs were evaluated in 127 genes from 6 major DNA repair pathways. Cumulative doses of chemotherapy and body region-specific radiotherapy (RT) were abstracted from medical records. Relative rates (RRs) and 95% CIs of SNs by mutation status were estimated using multivariable piecewise exponential models.
Of 4,402 survivors, 495 (11.2%) developed 1,269 SNs. We identified 538 PGMs in 98 DRGs (, , , and , among others) in 508 (11.5%) survivors. Mutations in homologous recombination (HR) genes were significantly associated with an increased rate of subsequent female breast cancer (RR, 3.7; 95% CI, 1.8 to 7.7), especially among survivors with chest RT ≥ 20 Gy (RR, 4.4; 95% CI, 1.6 to 12.4), or with a cumulative dose of anthracyclines in the second or third tertile (RR, 4.4; 95% CI, 1.7 to 11.4). Mutations in HR genes were also associated with an increased rate of subsequent sarcoma among those who received alkylating agent doses in the third tertile (RR, 14.9; 95% CI, 4.0 to 38.0). Mutations in nucleotide excision repair genes were associated with subsequent thyroid cancer for those treated with neck RT ≥ 30 Gy (RR, 12.9; 95% CI, 1.6 to 46.6) with marginal statistical significance.
Our study provides novel insights regarding the contribution of genetics, in combination with known treatment-related risks, for the development of SNs. These findings have the potential to facilitate identification of high-risk survivors who may benefit from genetic counseling and/or testing of DRGs, which may further inform personalized cancer surveillance and prevention strategies.
研究癌症治疗与 DNA 修复基因（DRG）中的致病性种系突变（PGM），以鉴定有发生后续肿瘤（SN）风险增加的儿童癌症幸存者。
对圣裘德终身队列中幸存者的血液衍生 DNA 进行全基因组测序。评估了来自 6 个主要 DNA 修复途径的 127 个基因中的 PGM。从病历中提取化疗和身体特定区域放疗（RT）的累积剂量。使用多变量分段指数模型估计突变状态下 SN 的相对风险率（RR）和 95%置信区间（CI）。
在 4402 名幸存者中，有 495 名（11.2%）发生了 1269 次 SN。我们在 508 名（11.5%）幸存者中发现了 98 个 DRG 中的 538 个 PGM（HR、ATM、BRCA1、BRCA2 等）。同源重组（HR）基因突变与女性乳腺癌后续发病率的增加显著相关（RR，3.7；95%CI，1.8 至 7.7），尤其是胸部 RT≥20Gy 的幸存者（RR，4.4；95%CI，1.6 至 12.4）或蒽环类药物累积剂量处于第二或第三 tertile 的幸存者（RR，4.4；95%CI，1.7 至 11.4）。在接受第三 tertile 烷化剂剂量的患者中，HR 基因突变也与肉瘤的后续发病率增加相关（RR，14.9；95%CI，4.0 至 38.0）。对于接受颈部 RT≥30Gy 的患者，核苷酸切除修复基因的突变与甲状腺癌的后续发生相关（RR，12.9；95%CI，1.6 至 46.6），具有边缘统计学意义。
我们的研究提供了有关遗传因素与已知治疗相关风险相结合对 SN 发展的贡献的新见解。这些发现有可能帮助鉴定高风险幸存者，他们可能受益于遗传咨询和/或 DRG 测试，这可能进一步为个性化癌症监测和预防策略提供信息。
