Yang Soo-Ryum, Gedvilaite Erika, Ptashkin Ryan, Chang Jason, Ziegler John, Mata Douglas A, Villafania Liliana B, Nafa Khedoudja, Hechtman Jaclyn F, Benayed Ryma, Zehir Ahmet, Benhamida Jamal, Arcila Maria E, Mandelker Diana, Rudin Charles M, Paik Paul K, Drilon Alexander, Schoenfeld Adam J, Ladanyi Marc
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
J Thorac Oncol. 2024 Mar;19(3):409-424. doi: 10.1016/j.jtho.2023.10.004. Epub 2023 Oct 12.
Microsatellite instability (MSI) and mismatch repair (MMR) deficiency represent a distinct oncogenic process and predict response to immune checkpoint inhibitors (ICIs). The clinicopathologic features of MSI-high (MSI-H) and MMR deficiency (MMR-D) in lung cancers remain poorly characterized.
MSI status from 5171 patients with NSCLC and 315 patients with SCLC was analyzed from targeted next-generation sequencing data using two validated bioinformatic pipelines.
MSI-H and MMR-D were identified in 21 patients with NSCLC (0.41%) and six patients with SCLC (1.9%). Notably, all patients with NSCLC had a positive smoking history, including 11 adenocarcinomas. Compared with microsatellite stable cases, MSI-H was associated with exceptionally high tumor mutational burden (37.4 versus 8.5 muts/Mb, p < 0.0001), MMR mutational signatures (43% versus 0%, p < 0.0001), and somatic biallelic alterations in MLH1 (52% versus 0%, p < 0.0001). Loss of MLH1 and PMS2 expression by immunohistochemistry was found in MLH1 altered and wild-type cases. Similarly, the majority of patients with MSI-H SCLC had evidence of MLH1 inactivation, including two with MLH1 promoter hypermethylation. A single patient with NSCLC with a somatic MSH2 mutation had Lynch syndrome as confirmed by the presence of a germline MSH2 mutation. Among patients with advanced MSI-H lung cancers treated with ICIs, durable clinical benefit was observed in three of eight patients with NSCLC and two of two patients with SCLC. In NSCLC, STK11, KEAP1, and JAK1 were mutated in nonresponders but wild type in responders.
We present a comprehensive clinicogenomic landscape of MSI-H lung cancers and reveal that MSI-H defines a rare subset of lung cancers associated with smoking, high tumor mutational burden, and MLH1 inactivation. Although durable clinical benefit to ICI was observed in some patients, the broad range of responses suggests that clinical activity may be modulated by co-mutational landscapes.
微卫星不稳定性（MSI）和错配修复（MMR）缺陷代表一种独特的致癌过程，并可预测对免疫检查点抑制剂（ICI）的反应。肺癌中微卫星高度不稳定（MSI-H）和错配修复缺陷（MMR-D）的临床病理特征仍未得到充分描述。
使用两种经过验证的生物信息学流程，从靶向二代测序数据中分析了5171例非小细胞肺癌（NSCLC）患者和315例小细胞肺癌（SCLC）患者的MSI状态。
在21例NSCLC患者（0.41%）和6例SCLC患者（1.9%）中鉴定出MSI-H和MMR-D。值得注意的是，所有NSCLC患者都有吸烟史，其中包括11例腺癌。与微卫星稳定病例相比，MSI-H与极高的肿瘤突变负荷（37.4对8.5个突变/Mb，p<0.0001）、MMR突变特征（43%对0%，p<0.0001）以及MLH1中的体细胞双等位基因改变（52%对0%，p<0.0001）相关。在MLH1改变和野生型病例中，通过免疫组化发现MLH1和PMS2表达缺失。同样，大多数MSI-H SCLC患者有MLH1失活的证据，包括2例MLH1启动子高甲基化患者。1例NSCLC患者存在体细胞MSH2突变，经种系MSH2突变证实患有林奇综合征。在接受ICI治疗的晚期MSI-H肺癌患者中，8例NSCLC患者中有3例、2例SCLC患者中有2例观察到持久的临床获益。在NSCLC中，无反应者的STK11、KEAP1和JAK1发生突变，而反应者为野生型。
我们展示了MSI-H肺癌的全面临床基因组图谱，并揭示MSI-H定义了一组与吸烟、高肿瘤突变负荷和MLH1失活相关的罕见肺癌亚型。尽管在一些患者中观察到对ICI的持久临床获益，但广泛的反应表明临床活性可能受共突变图谱的调节。
