ImportanceMicrosatellite (MS) instability (MSI-H) occurs frequently in Lynch syndrome (LS)–associated tumors and is associated with response to immune checkpoint blockade (ICB) therapy. MSI-H is conferred by germline or somatic variants in mismatch repair genes. The contribution of somatic oncogenesis to MSI-H in pancreatic cancer (PC) is unknown.ObjectiveTo evaluate an LS-related PC cohort to define clinicogenomic features, describe somatic MSI-H cases (germline negative), characterize response to ICB, and guide preferred MS testing methods.Design, Setting, and ParticipantsThis single-institution, retrospective analysis was conducted from March 2012 to July 2023 at Memorial Sloan Kettering Cancer Center and included 55 patients with PC and either an LS germline pathogenic variant (gPV) or somatic mismatch repair (MMR) variant.Main Outcomes and MeasuresComposite MMR and MS status determined using orthogonal methods. An artificial intelligence classifier was used to account for low-cellularity specimens. Demographic and clinical data were abstracted from medical record. Zygosity status and somatic comutation landscape analyzed.ResultsFifty-five patients (23 women [42%]) had PC and an MMR variant: 32 (58%) had LS (LS cohort) and 23 (42%) had a somatic MMR variant (no germline pathogenic variant, somatic MMR cohort). In the LS cohort, 10 (31%) had gMSH2, 9 (28%) gMSH6, 8 (25%) gPMS2, 4 (13%) gMLH1, 1 (3%) gEPCAM. The median age at diagnosis was 68 years (range, 45-88 years). For composite MS status, 17 (59%) were MSI-H, 12 (41%) MS stable, and 3 MS unknown. Five cases were reclassified as MSI-H by the artificial intelligence classifier. In the somatic MMR cohort, 11 (48%) had MSH6, 7 (30%) MLH1, 3 (13%) MSH2, and 2 (9%) PMS2. The median age at diagnosis was 72 years (range, 66-85 years). For composite MS status, 10 (43%) were MSI-H, 11 (48%) MS stable, and 2 (9%) MS indeterminate. Six cases were reclassified as MSI-H by the artificial intelligence classifier. For the LS and somatic MMR cohorts, 20 received ICB (n = 17 MSI-H). The median ICB duration was 27.7 months (95% CI, 11.5 to not reached); the disease control rate was 80%.ConclusionThe results of this cross-sectional study suggest that MSI-H occurs due to LS or somatic oncogenesis in PC. Orthogonal MS testing is key in PC; the artificial intelligence classifier reclassified approximately 20% of cases, most of which were low cellularity. ICB for patients with LS or somatic MSI-H PC provided significant benefit.

中文翻译：

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林奇综合征和胰腺癌的体细胞错配修复变异


重要性微卫星 (MS) 不稳定性 (MSI-H) 经常发生在林奇综合征 (LS) 相关肿瘤中，并且与免疫检查点阻断 (ICB) 治疗的反应相关。 MSI-H 是由错配修复基因中的种系或体细胞变异赋予的。体细胞肿瘤发生对胰腺癌 (PC) MSI-H 的贡献尚不清楚。 目的评估 LS 相关的 PC 队列，以确定临床基因组特征，描述体细胞 MSI-H 病例（种系阴性），描述对 ICB 的反应，并指导首选MS 测试方法。设计、设置和参与者这项单机构回顾性分析于 2012 年 3 月至 2023 年 7 月在纪念斯隆凯特琳癌症中心进行，包括 55 名患有 PC 和 LS 种系致病性变异 (gPV) 或体细胞错配修复的患者(MMR) 变体。主要结果和措施使用正交方法确定综合 MMR 和 MS 状态。使用人工智能分类器来解释低细胞样本。人口统计和临床数据是从病历中提取的。分析接合性状态和体细胞突变情况。 结果 55 名患者（23 名女性 [42%]）患有 PC 和 MMR 变异：32 名 (58%) 患有 LS（LS 队列），23 名 (42%) 患有体细胞 MMR 变异（无种系致病变异，体细胞 MMR 队列）。在 LS 队列中，10 例（31%）有 gMSH2，9 例（28%）gMSH6，8 例（25%）gPMS2，4 例（13%）gMLH1，1 例（3%）gEPCAM。诊断时的中位年龄为 68 岁（范围：45-88 岁）。对于复合 MS 状态，17 例 (59%) 为 MSI-H，12 例 (41%) MS 稳定，3 例 MS 未知。人工智能分类器将 5 例重新分类为 MSI-H。在体细胞 MMR 队列中，11 例 (48%) 具有 MSH6、7 例 (30%) MLH1、3 例 (13%) MSH2 和 2 例 (9%) PMS2。 诊断时的中位年龄为 72 岁（范围为 66-85 岁）。对于复合 MS 状态，10 例 (43%) 为 MSI-H，11 例 (48%) MS 稳定，2 例 (9%) MS 不确定。人工智能分类器将 6 例重新分类为 MSI-H。对于 LS 和体细胞 MMR 队列，20 人接受了 ICB（n = 17 MSI-H）。中位 ICB 持续时间为 27.7 个月（95% CI，11.5 至未达到）；疾病控制率为80%。结论这项横断面研究的结果表明MSI-H的发生是由于LS或PC中的体细胞肿瘤发生。正交 MS 测试是 PC 中的关键；人工智能分类器重新分类了大约 20% 的病例，其中大多数是低细胞含量的病例。 ICB 为 LS 或体细胞 MSI-H PC 患者提供了显着的益处。