Abstract Introduction Actionable somatic molecular alterations are found in 15% to 20% of NSCLC in Europe. NSCLC is a tumor observed in patients with germline TP53 variants causing Li-Fraumeni syndrome (LFS), but its somatic molecular profile is unknown. Methods Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants. Results Among 22 patients with NSCLC and LFS (n = 23 lung tumors), 64% were women, median age was 51 years, 84% were nonsmokers, 73% had adenocarcinoma histological subtype, and 84% were diagnosed with advanced-stage disease. These patients harbored 16 distinct germline TP53 variants; the most common was p.R158H (5/22; three in the same family). Personal and family histories of cancer were reported in 71% and 90% of patients, respectively. In most cases (87%, 13/15), lung cancer was diagnosed with a late onset. Of the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19 of 21 (90%), EGFR mutations in 18 (exon 19 deletion in 12 cases, L858R in three cases, and G719A, exon 20 insertion, and missing mutation subtype, each with one case), and ROS1 fusion in one case. A PI3KCA mutation was concurrently detected at diagnosis in three EGFR exon 19-deleted tumors (3/12). The median overall survival was 37.3 months in 14 patients treated with EGFR inhibitors; seven developed resistance, five (71%) acquired EGFR-T790M mutation, and one had SCLC transformation. Conclusions Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations; one ROS1 fusion was also observed. The germline TP53 variants and lung cancer carcinogenesis driven by oncogenic processes need further evaluation.

中文翻译：

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简报：Li-Fraumeni 综合征非小细胞肺癌患者体细胞致癌驱动基因改变的高患病率

摘要 介绍 在欧洲 15% 到 20% 的 NSCLC 中发现了可行的体细胞分子改变。NSCLC 是一种在具有生殖系 TP53 变异的患者中观察到的肿瘤，导致 Li-Fraumeni 综合征 (LFS)，但其体细胞分子谱未知。方法 回顾性研究 NSCLC 和胚系 TP53 变异患者的临床和分子特征。结果 22 例 NSCLC 和 LFS 患者（n = 23 肺肿瘤）中，64% 为女性，中位年龄为 51 岁，84% 为非吸烟者，73% 为腺癌组织学亚型，84% 被诊断为晚期疾病。这些患者携带 16 个不同的生殖系 TP53 变体；最常见的是 p.R158H（5/22；三个在同一家族中）。分别有 71% 和 90% 的患者报告了个人和家族癌症病史。在大多数情况下（87%，13/15），肺癌被诊断为晚发型。在分析的 21 种肿瘤中，21 例中有 19 例（90%）发现体细胞致癌驱动突变，18 例发现 EGFR 突变（12 例外显子 19 缺失，3 例 L858R，以及 G719A、外显子 20 插入和缺失突变亚型，每一种情况），以及一种情况下的 ROS1 融合。在诊断时在三个 EGFR 外显子 19 缺失的肿瘤中同时检测到 PI3KCA 突变 (3/12)。14 名接受 EGFR 抑制剂治疗的患者的中位总生存期为 37.3 个月；7 人产生耐药性，5 人（71%）获得 EGFR-T790M 突变，1 人发生 SCLC 转化。结论 在 90% 的 LFS 肿瘤中观察到驱动致癌改变，主要是 EGFR 突变；还观察到一种 ROS1 融合。