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Abstract：
Patients with pancreatic cancer (PC) showing mismatch repair (MMR) deficiency may benefit from immunotherapy. Microsatellite instability (MSI) is a hallmark of MMR deficiency (MMR-D). Here, we estimated the prevalence of MSI in PC, investigated germline and somatic mutations in the three MMR genes (MLH1, MSH2, and MSH6), and assessed the relationship between MMR genes mutations and MSI status in PC. Clinical specimens from PC patients were analyzed using targeted next-generation sequencing, including paired normal and tumor specimens from 155 patients, tumor-only specimens from 86 patients, and normal-only specimens from 379 patients. The MSI status of 235 PCs was assessed via PCR. Pathogenic/likely pathogenic (P/LP) germline variants in the MMR genes were identified in 1.1% of patients, while somatic variants were found in 2.6% of patients. No MSI-H tumors were detected. One patient carried two variants (P (VAF = 0.57) and LP (VAF = 0.25)) simultaneously; however, their germline/somatic status remains unknown due to the investigation focusing solely on the tumor and MSI analysis was not performed for this patient. MSI is rare in PC, even in tumors with MMR genes mutations. Our findings underscore the importance of assessing tumor MMR-D status in PC patients with confirmed Lynch syndrome when deciding whether to prescribe immunotherapy.
摘要：
显示错配修复（MMR）缺陷的胰腺癌（PC）患者可能会从免疫疗法中受益。微卫星不稳定性(MSI)是MMR缺陷(MMR-D)的标志。这里,我们估计了PC中MSI的患病率，研究了三个MMR基因（MLH1，MSH2和MSH6）中的种系和体细胞突变，并评估了PC中MMR基因突变与MSI状态之间的关系。使用靶向下一代测序分析PC患者的临床标本，包括155例患者的配对正常和肿瘤标本，来自86例患者的肿瘤标本，和379例患者的正常标本。通过PCR评估235个PC的MSI状态。在1.1％的患者中发现MMR基因中的致病性/可能致病性（P/LP）种系变异，而在2.6%的患者中发现了体细胞变异。未检测到MSI-H肿瘤。一名患者同时携带两种变体（P（VAF=0.57）和LP（VAF=0.25））；然而，他们的种系/体细胞状态仍然未知,因为本研究仅关注肿瘤,并且未对该患者进行MSI分析.MSI在PC中很少见，甚至在MMR基因突变的肿瘤中。我们的发现强调了在决定是否开免疫治疗时，评估确诊为Lynch综合征的PC患者肿瘤MMR-D状态的重要性。
