评估不同的林奇综合征（LS）筛查方法并建立有效且灵敏的策略对于临床实践至关重要。复旦大学附属肿瘤医院总共招募了 583 名结直肠癌 (CRC) 患者。通过免疫组织化学 (IHC) 和下一代测序 (NGS) 检查患者样本，并在 MLH1 缺陷病例中检测到 MLH1 启动子高甲基化 (MPH)。在存在有害变异的病例中进行种系基因检测，在没有 MMR 种系变异的 dMMR 或 MSI-H 病例中检测到肿瘤 MMR 基因的大基因组重排 (LGR)。我们的结果显示，通过 IHC 分类并随后进行 BRAF/MLH1 甲基化测试（策略 1），识别出 93.3% (70/75) 的 LS 病例。 IHC 随后进行种系 NGS（策略 2）或直接肿瘤 NGS（策略 3）均鉴定出 98.7% (74/75) 的 LS 病例。 LS病例中LGR的比例为16.0%（12/75），而84.0%（63/75）显示SNV/Indel。策略1、策略2和策略3的每位患者的平均费用分别为6010.81元、6058.48元和8029.98元。每个患者在不同策略上花费的平均时间分别为 4.74 天（策略 1）、4.89 天（策略 2）和 14.50 天（策略 3）。 LS 和林奇样综合征 (LLS) 的发病年龄比 MPH 更早。总之，我们比较了 LS 筛查的不同工作流程，考虑到灵敏度、时间和成本，建议使用 IHC 加种系 NGS 进行 LS 筛查。此外，多重连接依赖性探针扩增弥补了NGS的缺点，应纳入常规筛查。© 2024 作者。约翰·威利出版的《国际癌症杂志》

To evaluate different Lynch syndrome (LS) screening approaches and establish an efficient and sensitive strategy are critical for clinical practice. In total, 583 patients with colorectal carcinoma (CRC) at Fudan University Shanghai Cancer Center were enrolled. Patient samples were examined by immunohistochemistry (IHC) and next-generation sequencing (NGS), and MLH1 promoter hypermethylation (MPH) was detected in MLH1-deficient cases. Germline genetic testing was performed in cases with deleterious variants and large genomic rearrangements (LGRs) of tumor MMR genes were detected in cases with dMMR or MSI-H cases with no MMR germline variants. Our results showed that triage with IHC and followed by BRAF/MLH1 methylation testing (Strategy 1) identified 93.3% (70/75) of LS cases. IHC followed by germline NGS (Strategy 2) or direct tumor NGS (Strategy 3) both identified 98.7% (74/75) of LS cases. The proportion of LGRs in LS cases was 16.0% (12/75), while 84.0% (63/75) showed SNV/Indel. The average cost per patient was ¥6010.81, ¥6058.48, and ¥8029.98 for Strategy 1, Strategy 2 and Strategy 3, respectively. The average time spent on different strategies was 4.74 days (Strategy 1), 4.89 days (Strategy 2), and 14.50 days (Strategy 3) per patient, respectively. LS and Lynch-like syndrome (LLS) were associated with an earlier onset age than MPH. In conclusion, we compared different workflows for LS screening and IHC plus germline NGS is recommended for LS screening when taking sensitivity, time, and cost into account. Moreover, multiplex ligation-dependent probe amplification made up for the shortcoming of NGS and should be incorporated into routine screening.© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.