Introduction: Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS‐mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer‐related co‐mutations and their correlation with different KRAS mutation subtypes. Methods: Diagnostic samples from 4507 patients with NSCLC were analyzed by next‐generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next‐generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole‐exome sequencing was performed in two patients. Results: We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co‐occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb‐b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co‐occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole‐exome sequencing of two patients with co‐occurring phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds. Conclusion: KRAS‐mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co‐occurring mutations in cancer‐associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS‐mutated NSCLC and for future trial design.

中文翻译：

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NSCLC 中的 K-ras 突变亚型和其他致癌途径中的相关共发生突变

简介：虽然长期以来 NSCLC 中的 KRAS 突变被认为是相互排斥的驱动突变，但现在越来越多的证据表明 KRAS 突变的 NSCLC 代表了一个遗传异质亚组。我们试图确定癌症相关共突变的遗传异质性及其与不同 KRAS 突变亚型的相关性。方法：通过下一代测序分析来自 4507 名 NSCLC 患者的诊断样本，使用一组 14 个基因，并在一部分患者中进行荧光原位杂交。在 101 名患者中进行了包含 14 个额外基因的扩展组的下一代测序。分子数据与临床数据相关。对两名患者进行了全外显子组测序。结果：我们确定了 1078 名 KRAS 突变患者，其中 53 名。5% 至少有一个额外的突变。不同的 KRAS 突变亚型显示出不同的共发生突变模式。除了肿瘤蛋白 p53 基因 (TP53) (39.4%)、丝氨酸/苏氨酸激酶 11 基因 (STK11) (19.8%)、kelch 样 ECH 相关蛋白 1 基因 (KEAP1) (12.9%) 和 ATM 丝氨酸/苏氨酸激酶的突变基因（ATM）（11.9%），以及 MNNG HOS 转化基因（MET）扩增（15.4%）和 erb-b2 受体酪氨酸激酶 2 基因（ERBB2）扩增（13.8%，仅在 G12C 中），我们发现了罕见的 co -EGFR (1.2%) 和 BRAF (1.2%) 中可靶向突变的发生。对同时发生磷脂酰肌醇-4,5-二磷酸 3-激酶催化亚基 α 基因 (PIK3CA) 突变的两名患者的全外显子组测序显示，一名患者具有突变 KRAS 的克隆性，第二名患者具有亚克隆性，暗示了不同的进化背景。结论：KRAS 突变的 NSCLC 代表了一个基因异质亚组，在癌症相关通路中具有高频率的共同发生突变，部分与不同的 KRAS 突变亚型相关。这种多样性可能对理解 KRAS 突变的 NSCLC 治疗结果的可变性和未来的试验设计有影响。