Data from: Landscape of tumor mutation load, mismatch repair deficiency, and PD-L1 expression in a large patient cohort of gastrointestinal cancers

Purpose: The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency status (dMMR), and programmed cell death-ligand 1 (PD-L1) expression. Herein, we attempt to quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Experimental Design: A total of 4125 tumors from 14 different gastrointestinal cancer sites were studied. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor samples using the NextSeq platform. TML was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Microsatellite instability (MSI) was assessed by validated direct analysis of altered known MSI loci in the target regions of the sequenced genes. PD-L1 expression was analyzed by immunohistochemistry. Results: Right-sided colon and small bowel adenocarcinomas had the highest prevalence of TML-high tumors (14.6% and 10.2%, respectively). Pancreatic neuroendocrine tumors and gastrointestinal stromal tumors (GIST) had the lowest rates of TML-high (1.3% and 0%, respectively). TML-high status was strongly associated with MSI-H (P<0.0001). However, all TML-high anal cancers (8.3%) were microsatellite stable (MSS). Higher PD-L1 expression was more likely to be seen in MSI compared with MSS tumors (20.6% vs. 7.8%, P<0.0001). Conclusions: TML-high rate varied widely among gastrointestinal cancers. Although microsatellite instability is conceivably the main driver for TML-high status, other factors may be involved. Future clinical trials are needed to evaluate whether the integration of TML, MSI, and PD-L1 could better identify potential responders to immunotherapy.研究目的：免疫治疗在不同胃肠道肿瘤中的疗效差异显著。已有研究证实，肿瘤突变负荷（Tumor Mutation Load, TML）、错配修复缺陷（mismatch repair deficiency, dMMR）状态与程序性死亡配体1（programmed cell death-ligand 1, PD-L1）的表达水平，均与免疫检查点抑制剂的临床应答密切相关。本研究旨在量化胃肠道肿瘤中的TML、dMMR及PD-L1表达水平，并明确三者之间的相互关联。 实验设计：本研究共纳入来自14种不同胃肠道肿瘤部位的4125例肿瘤样本。采用NextSeq测序平台，对福尔马林固定石蜡包埋（formalin-fixed paraffin-embedded, FFPE）肿瘤样本中提取的基因组DNA进行二代测序（next-generation sequencing, NGS）。TML的计算仅基于592基因panel测序获得的体细胞非同义错义突变。微卫星不稳定（microsatellite instability, MSI）通过对测序基因靶区域内已知MSI位点的变异进行验证性直接分析完成评估。PD-L1表达水平采用免疫组化法进行检测。 结果：右侧结肠腺癌与小肠腺癌的TML高表达（TML-high）肿瘤患病率最高，分别为14.6%与10.2%。胰腺神经内分泌肿瘤与胃肠道间质瘤（gastrointestinal stromal tumor, GIST）的TML高表达率最低，分别为1.3%与0%。TML高表达状态与MSI高度不稳定（MSI-H）显著相关（P<0.0001）。但所有TML高表达的肛门癌（8.3%）均为微卫星稳定（microsatellite stable, MSS）。与微卫星稳定肿瘤相比，微卫星不稳定肿瘤的PD-L1高表达比例更高（20.6% vs. 7.8%，P<0.0001）。 结论：胃肠道肿瘤的TML高表达率存在显著异质性。尽管微卫星不稳定被认为是TML高表达状态的主要驱动因素，但可能存在其他潜在调控因素。未来需开展临床试验，评估整合TML、MSI与PD-L1指标是否能够更精准地筛选免疫治疗潜在应答人群。