Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD 20892, USA.
Genetics Branch, Center for Cancer Research, NCI, Bethesda, MD 20892, USA.
Sci Transl Med. 2021 Jan 27;13(578). doi: 10.1126/scitranslmed.abc7488.
Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. To assess the extent of inherited susceptibility to small cell lung cancer (SCLC), the most lethal type of lung cancer, we sequenced germline exomes of 87 patients (77 SCLC and 10 extrapulmonary small cell) and considered 607 genes, discovering 42 deleterious variants in 35 cancer-predisposition genes among 43.7% of patients. These findings were validated in an independent cohort of 79 patients with SCLC. Loss of heterozygosity was observed in 3 of 14 (21.4%) tumors. Identification of variants influenced medical management and family member testing in nine (10.3%) patients. Unselected patients with SCLC were more likely to carry germline RAD51 paralog D (), checkpoint kinase 1 (), breast cancer 2 (), and mutY DNA glycosylase () pathogenic variants than healthy controls. Germline genotype was significantly associated with the likelihood of a first-degree relative with cancer or lung cancer (odds ratio: 1.82, = 0.008; and 2.60, = 0.028), and longer recurrence-free survival after platinum-based chemotherapy ( = 0.002), independent of known prognostic factors. Treatment of a patient with relapsed SCLC and germline pathogenic mutation of interacting protein C-terminal helicase 1 (), a homologous recombination-related gene, using agents synthetically lethal with homologous recombination deficiency, resulted in a notable disease response. This work demonstrates that SCLC, currently thought to result almost exclusively from tobacco exposure, may have an inherited predisposition and lays the groundwork for targeted therapies based on the genes involved.
由于烟草是一种强有力的致癌物质，因此肺癌的次要病因在人们的认知中往往显得不那么重要。为了评估小细胞肺癌（SCLC）——最致命的肺癌类型——的遗传易感性程度，我们对 87 名患者（77 名 SCLC 和 10 名非肺部小细胞癌）的种系外显子组进行了测序，并考虑了 607 个基因，在 43.7%的患者中发现了 35 个癌症易感基因中的 42 个有害变异。这些发现在 79 名 SCLC 患者的独立队列中得到了验证。在 3 个肿瘤中观察到杂合性缺失。在 9 名（10.3%）患者中，鉴定出的变体影响了医疗管理和家庭成员检测。未经选择的 SCLC 患者携带种系 RAD51 等位基因 D（）、检查点激酶 1（）、乳腺癌 2（）和 mutY DNA 糖基化酶（）致病性变体的可能性高于健康对照。种系基因型与一级亲属患有癌症或肺癌的可能性显著相关（优势比：1.82， = 0.008；和 2.60， = 0.028），并且在铂类化疗后无复发生存期更长（ = 0.002），独立于已知的预后因素。对一名携带种系致病性突变的复发性 SCLC 患者（交互蛋白 C 端解旋酶 1（），一种同源重组相关基因）进行治疗，使用与同源重组缺陷合成致死的药物进行治疗，导致疾病显著缓解。这项工作表明，目前认为几乎完全由烟草暴露引起的 SCLC 可能具有遗传易感性，并为基于涉及的基因的靶向治疗奠定了基础。
