Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer
Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer
复制标题
DOI：
10.1200/jco.18.00283
复制
发表时间：
2019-02-01
影响因子：
45.3
通讯作者：
Stadler, Zsofia K.
中科院分区：
文献类型：
--
作者：
Latham, Alicia;Srinivasan, Preethi;Stadler, Zsofia K.
目的微卫星不稳定性(MSI)和/或错配修复缺陷(MMR-D)检测在结直肠癌(CRC)和子宫内膜癌(EC)患者中传统上用于筛查Lynch综合征(LS)相关的癌症易感性。最近在高频MSI(MSI-H)和/或MMR-D肿瘤中免疫治疗的成功现在支持在所有晚期实体肿瘤中进行MSI检测。LS在不同肿瘤类型中对MSI-H的影响程度尚不清楚。在这里，我们根据MSI状态确定LS在实体肿瘤中的患病率。方法使用下一代靶向测序确定MSI状态，肿瘤被归类为MSI-H、MSI-不确定或微卫星稳定。分析配对的胚系DNA中LS相关错配修复基因(MLH1、MSH2、MSH6、PMS2、EpCAM)的突变。结果在15,045例患者(50多种肿瘤类型)中，MSI-H、MSI不确定和微卫星稳定的肿瘤患者中，LS的阳性率分别为16.3%(53/326)、1.9%(13/699)和0.3%(37/14,020)(P<0.05)。
PURPOSE Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status.METHODS MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed.RESULTS Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively (P