癌症中的致病变异 ATM 基因与放射治疗疗效的遗传学基础。
Pathogenic ATM Mutations in Cancer and a Genetic Basis for Radiotherapeutic Efficacy.
机构信息
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
出版信息
J Natl Cancer Inst. 2021 Mar 1;113(3):266-273. doi: 10.1093/jnci/djaa095.
BACKGROUND
Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure.
METHODS
We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided.
RESULTS
Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors.
CONCLUSIONS
We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT.
背景
放射疗法是最常用的癌症治疗方法之一，但临床获益的遗传决定因素仍未得到充分描述。已知 ATM 的致病性种系变体可导致共济失调毛细血管扩张症，这是一种罕见的遗传性综合征，其特征是明显的辐射敏感性。相比之下，ATM 的体细胞失活是多种癌症中的常见事件，但它的临床可操作性仍不清楚。
方法
我们分析了作为机构基因组分析计划的一部分接受靶向基因组测序的 20107 名连续治疗的晚期癌症患者，并确定了 1085 名携带种系或体细胞 ATM 突变的患者，其中 357 名接受了放射治疗（RT）。携带 ATM 功能丧失（LoF）突变的照射肿瘤的结果与携带意义不明的变体的肿瘤进行了比较。所有统计检验均为双侧。
结果
在 357 名接受 727 次 RT 的泛癌患者中，ATM 的遗传失活与放射治疗疗效的改善相关。携带 ATM LoF 的照射肿瘤的 2 年累积肿瘤进展发生率为 13.2%，而携带意义不明变体的肿瘤为 27.5%（风险比 [HR] = 0.51，95%置信区间 [CI] = 0.34 至 0.77，P =.001）。在携带双等位基因 ATM 失活的肿瘤中观察到最大的临床获益（HR = 0.19，95%CI = 0.06 至 0.60，P =.005），在携带单等位基因 ATM 失活的肿瘤中也观察到统计学上显著的获益（HR = 0.57，95%CI = 0.35 至 0.92，P =.02）。值得注意的是，ATM LoF 在 TP53 野生型肿瘤中高度预测结局，但在 TP53 突变型肿瘤中则不然。
结论
我们证明了体细胞 ATM 失活与 RT 后肿瘤控制的显著改善相关。在多种癌症类型中鉴定出辐射敏感的肿瘤表型为基于基因组的 RT 提供了潜在的临床机会。
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