Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa.
IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Medical Oncology and Hematology Unit, Rozzano, Milan.
Eur J Cancer Prev. 2024 Jul 1;33(4):355-362. doi: 10.1097/CEJ.0000000000000870. Epub 2024 Jan 9.
Universal screening of colorectal cancer (CRC) patients for Lynch syndrome (LS) through MisMatch Repair (MMR) testing is recommended. BRAF V600E mutation and/or MLH1 promoter methylation (Reflex Testing, RefT)generally rule out LS in MLH1-deficient (dMLH1) patients. We estimated the impact of RefTon genetic counseling (GC) and on the diagnostic yield of genetic testing (GT).
Overall, 3199 CRC patients were referred to our center between 2011 and 2021. Patients referred until January 2019 (n=2536) underwent universal MMR testing and were termed 'Cohort A'; among patients after February 2019 (n=663), 'Cohort B', RefT was also performed in dMLH1 patients.
Overall, 401/3199 patients (12.5%) were MMR-deficient (dMMR); 312 (77.8%) in cohort A and 89 (22.2%) inB; 346/401 were dMLH1 (86.3%), 262/312 (83.9%) in cohort A and 84/89 (94.3%) in B. In Cohort A, 91/312 (29.1%) dMMR patients were referred to GC, 69/91 (75.8%) were in the dMLH1 group; 57/69 (82.6%) dMLH1 patients underwent GT and 1/57 (1.7%) had LS. In Cohort B, 3/84 dMLH1 patients did not undergo BRAF testing. Three BRAF wt and not hypermethylated of the remaining 81 dMLH1 patients were referred to GC and GT, and one had LS. This diagnostic pathway reduced GC referrals by 96% (78/81) in Cohort B and increased the diagnostic yield of GT by about 20 times.
Our findings support RefT in dMLH1 CRC patients within the LS diagnostic pathway, as it reduces the number of GC sessions needed and increases the diagnostic yield of GT.
通过错配修复（MMR）检测对结直肠癌（CRC）患者进行林奇综合征（LS）的普遍筛查是被推荐的。BRAF V600E 突变和/或 MLH1 启动子甲基化（Reflex Testing，RefT）通常可排除 MLH1 缺陷（dMLH1）患者的 LS。我们评估了 RefT 对遗传咨询（GC）的影响以及对基因检测（GT）诊断率的影响。
总体而言，2011 年至 2021 年间，我们中心共转介了 3199 例 CRC 患者。2019 年 1 月前转介的患者（n=2536）接受了普遍 MMR 检测，并被称为“队列 A”；2019 年 2 月后转介的患者（n=663），即“队列 B”，也对 dMLH1 患者进行了 RefT。
总体而言，3199 例患者中 401 例（12.5%）为 MMR 缺陷（dMMR）；队列 A 中有 312 例（77.8%），队列 B 中有 89 例（22.2%）；401 例患者中 346 例为 dMLH1（86.3%），队列 A 中有 262 例（83.9%），队列 B 中有 84 例（94.3%）。在队列 A 中，91/312（29.1%）的 dMMR 患者被转介至 GC，其中 69/91（75.8%）为 dMLH1 组；69 例 dMLH1 患者中有 57 例接受了 GT，其中 1 例为 LS。在队列 B 中，3/84 例 dMLH1 患者未接受 BRAF 检测。81 例 dMLH1 患者中，除 3 例 BRAFwt 且未甲基化的患者外，其余患者均被转介至 GC 和 GT，其中 1 例为 LS。这种诊断途径使队列 B 中的 GC 转介减少了 96%（78/81），并使 GT 的诊断率提高了约 20 倍。
我们的研究结果支持在 LS 诊断途径中对 dMLH1 CRC 患者进行 RefT，因为它减少了所需的 GC 次数，并提高了 GT 的诊断率。
