Lynch syndrome (LS) is associated with an increased lifetime risk of several cancers including colorectal (CRC), endometrial (EC), ovarian (OC), urinary (UT) and sebaceous tumors (ST). The benefit for universal screening in CRC and EC is well known. However, this benefit in other major lynch-associated tumors is unclear. We performed a systematic review of all published articles in the MEDLINE database between 2005 to 2017 to identify studies performing universal screening for LS in unselected CRC, EC, OC, UT and ST. All cases with MSI-H (instability in two or more markers) or missing one or more proteins on IHC testing were considered screening positive. Cases with MLH1 promoter hypermethylation or BRAF mutation positive were considered to have somatic mutations. A total of 3788 articles were identified in MEDLINE yielding 129 study arms from 113 studies. The overall pooled yield of universal LS screening and germline mismatch gene mutation was significantly different across the major LS-associated tumors (Mann Whitney test, p < 0.001). The pooled screening yield was highest in ST [52.5% (355/676), 95% CI 48.74–56.26%] followed by EC [22.65% (1142/5041), 95% CI 21.54–23.86%], CRC [11.9% (5649/47,545), 95% CI 11.61–12.19%], OC [11.29% (320/2833), 95% CI 10.13–12.47%] and UT [11.2% (31/276), 95% CI 7.48–14.92%]. ST also had the highest pooled germline positivity for mismatch repair gene mutation [18.8%, 33/176, 95%CI 13.03–24.57], followed by EC [2.6% (97/3765), 95% CI 2.09–3.11], CRC [1.8% (682/37,220), 95% CI 1.66–1.94%], UT [1.8%(3/164), 95% CI − 0.24–3.83%] and OC [0.83%(25/2983), 95% CI 0.48–1.12%]. LS screening in EC yielded significantly higher somatic mutations compared to CRC [pooled percentage 16.94% [(538/3176), 95%CI 15.60–18.20%] vs. 5.23% [(1639/26,152), 95% CI 4.93–5.47%], Mann Whitney test, p < 0.0001. Universal LS testing should be routinely performed in OC, UT and STs in addition to CRC and EC. Our findings also support consideration for IHC and somatic mutation testing before germline testing in EC due to higher prevalence of somatic mutations as well as germline testing in all patients with ST. Our results have implications for future design of LS screening programs and further studies are needed to assess the cost effectiveness and burden on genetic counselling services with expanded universal testing for LS.

Lynch 综合征 (LS) 与几种癌症的终生风险增加有关，包括结肠直肠癌 (CRC)、子宫内膜 (EC)、卵巢 (OC)、泌尿 (UT) 和皮脂腺肿瘤 (ST)。在 CRC 和 EC 中进行普遍筛查的好处是众所周知的。然而，在其他主要的 lynch 相关肿瘤中这种益处尚不清楚。我们对 2005 年至 2017 年间在 MEDLINE 数据库中发表的所有文章进行了系统评价，以确定在未选择的 CRC、EC、OC、UT 和 ST 中对 LS 进行普遍筛查的研究。所有具有 MSI-H（两种或多种标记物不稳定）或在 IHC 测试中缺失一种或多种蛋白质的病例均被视为筛查阳性。MLH1 启动子高甲基化或 BRAF 突变阳性的病例被认为具有体细胞突变。在 MEDLINE 中总共确定了 3788 篇文章，从 113 项研究中产生了 129 个研究组。通用 LS 筛查和种系错配基因突变的总体汇总产量在主要 LS 相关肿瘤中显着不同（Mann Whitney 检验，p < 0.001）。ST [52.5% (355/676), 95% CI 48.74–56.26%] 的汇总筛选率最高，其次是 EC [22.65% (1142/5041), 95% CI 21.54–23.86%], CRC [11.9% (5649/47,545), 95% CI 11.61–12.19%], OC [11.29% (320/2833), 95% CI 10.13–12.47%] 和 UT [11.2% (31/276), 95% CI 7.48–14.92 %]。ST 对错配修复基因突变的合并种系阳性率也最高 [18.8%, 33/176, 95%CI 13.03–24.57]，其次是 EC [2.6% (97/3765), 95% CI 2.09–3.11], CRC [1.8% (682/37,220), 95% CI 1.66–1.94%], UT [1.8%(3/164), 95% CI - 0.24–3.83%] 和 OC [0.83%(25/2983), 95% CI 0.48–1.12%]。与 CRC 相比，EC 中的 LS 筛查产生显着更高的体细胞突变 [汇总百分比 16.94% [(538/3176), 95%CI 15.60–18.20%] vs. 5.23% [(1639/26,152), 95% CI 4.93–5.47% ]，曼惠特尼检验，p < 0.0001。除 CRC 和 EC 外，还应在 OC、UT 和 ST 中常规进行通用 LS 测试。我们的研究结果还支持在 EC 种系检测之前考虑 IHC 和体细胞突变检测，因为所有 ST 患者的体细胞突变和种系检测的患病率较高。我们的结果对 LS 筛查计划的未来设计具有影响，需要进一步的研究来评估遗传咨询服务的成本效益和负担，以及扩大 LS 的通用检测。94% [(538/3176), 95%CI 15.60–18.20%] 与 5.23% [(1639/26,152), 95% CI 4.93–5.47%]，Mann Whitney 检验，p < 0.0001。除 CRC 和 EC 外，还应在 OC、UT 和 ST 中常规进行通用 LS 测试。我们的研究结果还支持在 EC 种系检测之前考虑 IHC 和体细胞突变检测，因为所有 ST 患者的体细胞突变和种系检测的患病率较高。我们的结果对 LS 筛查计划的未来设计具有影响，需要进一步的研究来评估遗传咨询服务的成本效益和负担，以及扩大 LS 的通用检测。94% [(538/3176), 95%CI 15.60–18.20%] 与 5.23% [(1639/26,152), 95% CI 4.93–5.47%]，Mann Whitney 检验，p < 0.0001。除 CRC 和 EC 外，还应在 OC、UT 和 ST 中常规进行通用 LS 测试。我们的研究结果还支持在 EC 种系检测之前考虑 IHC 和体细胞突变检测，因为所有 ST 患者的体细胞突变和种系检测的患病率较高。我们的结果对 LS 筛查计划的未来设计具有影响，需要进一步的研究来评估遗传咨询服务的成本效益和负担，以及扩大 LS 的通用检测。我们的研究结果还支持在 EC 种系检测之前考虑 IHC 和体细胞突变检测，因为所有 ST 患者的体细胞突变和种系检测的患病率较高。我们的结果对 LS 筛查计划的未来设计具有影响，需要进一步的研究来评估遗传咨询服务的成本效益和负担，以及扩大 LS 的通用检测。我们的研究结果还支持在 EC 种系检测之前考虑 IHC 和体细胞突变检测，因为所有 ST 患者的体细胞突变和种系检测的患病率较高。我们的结果对 LS 筛查计划的未来设计具有影响，需要进一步的研究来评估遗传咨询服务的成本效益和负担，以及扩大 LS 的通用检测。