KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS -mutated non–small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development. Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type. Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS -mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%). KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation. This article is featured in Highlights of This Issue, [p. 2315][1] [1]: /lookup/volpage/20/2315?iss=12

中文翻译：

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非小细胞肺癌中 KRAS 突变亚型的特征

KRAS 是 NSCLC 中最常见的突变致癌基因，直接 KRAS 抑制剂的开发重新引起了人们对该分子变异体的兴趣。不同的 KRAS 突变可能代表具有不同预后和治疗影响的独特生物学背景。我们试图在大型全国队列中描述晚期 KRAS 突变的非小细胞肺癌 (NSCLC) 的基因组景观，以帮助指导未来的治疗发展。使用 592 个基因的 DNA 下一代测序（Caris Life Sciences）获得了 17,095 个 NSCLC 标本的分子谱，并根据 KRAS 突变的存在和亚型进行分类。通过 KRAS 突变类型分析共同发生的基因组改变、肿瘤突变负荷 (TMB) 和 PD-L1 表达 [22C3，肿瘤比例评分 (TPS) 评分]。在队列中，4,706 (27. 5%) 样本携带 KRAS 突变。最常见的亚型是 G12C (40%)，其次是 G12V (19%) 和 G12D (15%)。KRAS 突变的患病率在腺癌中为 37.2%，在鳞状细胞癌中为 4.4%。高 TMB（≥10 个突变/Mb）和 PD-L1 表达率在 KRAS 突变亚型中各不相同。KRAS G12C 最有可能是 PD-L1 阳性（65.5% TPS ≥ 1%）和 PD-L1 高（41.3% TPS ≥ 50%）。STK11 在 8.6% 的 KRAS 野生型 NSCLC 中发生突变，但在 KRAS 突变型 NSCLC 中更常见，G13 突变率最高 (36.2%)。TP53 突变在 KRAS 野生型 NSCLC 中更为常见 (73.6%)。KRAS 突变亚型具有不同的共生突变和独特的基因组景观。这些差异在特定治疗干预背景下的临床相关性值得研究。这篇文章刊登在本期要闻中，[p。2315][1][1]:/lookup/volpage/20/2315?iss=12