Clinical Pan-Cancer Assessment of Mismatch Repair Deficiency Using Tumor-Only, Targeted Next-Generation Sequencing.
Clinical Pan-Cancer Assessment of Mismatch Repair Deficiency Using Tumor-Only, Targeted Next-Generation Sequencing.
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DOI：
10.1200/po.20.00185
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发表时间：
2020-11
影响因子：
4.6
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鉴于免疫检查点抑制剂在不确定肿瘤类型的错配修复缺陷(MMR-D)癌症患者中的监管批准，确定MMR-D的发生特征并开发经济有效的筛查方法变得重要。使用下一代测序(NGS)小组(OncoPanel)，我们开发了一种算法来识别肿瘤样本中的MMR-D频率，并将其应用于临床环境中，并进行了病理学家审查。为了预测MMR-D，我们采用了前面描述的方法用于NGS小组，该小组评估在均聚物区发生的单碱基对插入或缺失事件的模式。纳入2013年7月至2018年7月期间使用OncoPanel进行检测的肿瘤。对于2017年6月以后测试的肿瘤，测序结果被实时提交给病理学家，用于在肿瘤突变负担、其他突变特征和临床数据的背景下进行临床MMR测定。在测序的20,301个肿瘤中，2.7%(553个)被该算法回顾地归类为MMR-D。在4,404个病理学家签出MMR状态的样本中，该算法将147个(3.3%)归类为MMR-D：在116例中，MMR-D被病理学家确认，5例被病理学家否决，26例被评估为不确定。总体而言，OncoPanel推断的MMR-D在子宫内膜癌(21%；152/723)、结直肠癌(9.7%；169/1,744)和小肠癌(9.3%；9/97)中的频率最高。当将算法预测与历史的MMR免疫组织化学或聚合酶链式反应结果相比较时，在病理学家评估开始之前对325个肿瘤进行测序，该算法的总体灵敏度和特异度分别为91.1%和98.2%。我们表明，靶向的、仅针对肿瘤的NGS可以被用来确定不同肿瘤类型的MMR信号，这表明更广泛的生物标志物筛选方法可能具有临床价值。
Given regulatory approval of immune checkpoint inhibitors in patients with mismatch repair–deficient (MMR-D) cancers agnostic to tumor type, it has become important to characterize occurrence of MMR-D and develop cost-effective screening approaches. Using a next-generation sequencing (NGS) panel (OncoPanel), we developed an algorithm to identify MMR-D frequency in tumor samples and applied it in a clinical setting with pathologist review. To predict MMR-D, we adapted methods described previously for use in NGS panels, which assess patterns of single base-pair insertion or deletion events occurring in homopolymer regions. Tumors assayed with OncoPanel between July 2013 and July 2018 were included. For tumors tested after June 2017, sequencing results were presented to pathologists in real time for clinical MMR determination, in the context of tumor mutation burden, other mutational signatures, and clinical data. Of 20,301 tumors sequenced, 2.7% (553) were retrospectively classified as MMR-D by the algorithm. Of 4,404 samples with pathologist sign-out of MMR status, the algorithm classified 147 (3.3%) as MMR-D: in 116 cases, MMR-D was confirmed by a pathologist, five cases were overruled by the pathologist, and 26 were assessed as indeterminate. Overall, the highest frequencies of OncoPanel-inferred MMR-D were in endometrial (21%; 152/723), colorectal (9.7%; 169/1,744), and small bowel (9.3%; 9/97) cancers. When algorithm predictions were compared with historical MMR immunohistochemistry or polymerase chain reaction results in a set of 325 tumors sequenced before initiation of pathologist assessment, the overall sensitivity and specificity of the algorithm were 91.1% and 98.2%, respectively. We show that targeted, tumor-only NGS can be leveraged to determine MMR signatures across tumor types, suggesting that broader biomarker screening approaches may have clinical value.