机构：[1]Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China[2]Geneplus-Beijing Institute, Beijing, China[3]Department of Surgery, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China[4]Departments of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China[5]Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China[6]Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, China病理科[7]Houston Methodist Research Institute, Houston, TX, USA[8]Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA[9]Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA[10]Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA[11]Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Oncogenic fusions are rare in colorectal carcinomas, but may be important for prognosis and therapy. An effective strategy for screening targetable oncogenic fusions in colorectal carcinomas is needed. Here, we investigate molecular genetic alterations in colorectal carcinomas based on their DNA mismatch repair status, and to effectively screen for targetable oncogenic fusions in colorectal carcinomas. In this retrospective study, the initial cohort included 125 consecutive mismatch repair-deficient and 238 randomly selected mismatch repair-proficient colorectal carcinomas diagnosed between July 2015 and December 2017 at Peking Union Medical College Hospital. Targeted sequencing was performed. MLH1 promoter hypermethylation analysis was further employed for subgrouping dMMR colorectal carcinomas. Clinicopathological characteristics, molecular features, and survival outcome of colorectal carcinomas harboring oncogenic fusions were assessed. A multicenter cohort comprised of 227 colorectal carcinomas with dual loss of MLH1/PMS2 was used to validate the efficacy of the proposed screening strategy for oncogenic fusions. Of the 363 patients in the initial cohort, 11(3.0%) harbored oncogenic fusions and were all mismatch repair-deficient colorectal carcinomas with hypermethylated MLH1 and wild-type BRAF and KRAS, comprising 55% (11/20) of this subgroup. These patients with oncogenic fusions showed poorer 3-year cancer-specific survival compared with other Stage III/IV mismatch repair-deficient colorectal carcinoma patients (40% vs. 97%), and significantly higher CD274(PD-L1) expression in tumor cells compared with other dMMR colorectal carcinoma patients (46% vs. 6.1%, P < 0.001). An easy-to-perform and cost-efficient strategy for screening targetable fusions was proposed based on the current molecular testing algorithms for colorectal carcinomas, and validated in an independent multicenter cohort. In conclusion, oncogenic fusions were highly enriched and frequently detected in mismatch repair-deficient colorectal carcinomas with MLH1 hypermethylation and wild-type BRAF and KRAS, and were associated with poor prognosis and high tumor CD274(PD-L1) expression. ? 2019, United States & Canadian Academy of Pathology.
第一作者机构：[1]Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
共同第一作者：
通讯作者：
通讯机构：[1]Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
推荐引用方式(GB/T 7714)：
Jing Wang,Yuting Yi,Yi Xiao,et al.Prevalence of recurrent oncogenic fusion in mismatch repair-deficient colorectal carcinoma with hypermethylated MLH1 and wild-type BRAF and KRAS[J].Modern Pathology.2019,32(7):1053-1064.doi:10.1038/s41379-019-0212-1.
APA：
Jing Wang,Yuting Yi,Yi Xiao,Lin Dong,Li Liang...&Zhiyong Liang.(2019).Prevalence of recurrent oncogenic fusion in mismatch repair-deficient colorectal carcinoma with hypermethylated MLH1 and wild-type BRAF and KRAS.Modern Pathology,32,(7)
MLA：
Jing Wang,et al."Prevalence of recurrent oncogenic fusion in mismatch repair-deficient colorectal carcinoma with hypermethylated MLH1 and wild-type BRAF and KRAS".Modern Pathology 32..7(2019):1053-1064
医学