Prevalence of recurrent oncogenic fusion in mismatch repair-deficient colorectal carcinoma with hypermethylated MLH1 and wild-type BRAF and KRAS

Abstract

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 repairdeficient colorectal carcinomas with MLH1 hypermethylation and wild-type BRAF and KRAS, and were associated with poor prognosis and high tumor CD274(PD-L1) expression.

Distinct clinical phenotype and genetic testing strategy for Lynch syndrome in China based on a large colorectal cancer cohort

“…Analysis of MLH1 promoter methylation in this cohort after BRAF mutation detection significantly decreased the number of patients requiring genetic analysis by 23.8% more than BRAF mutation testing alone in the MLH1‐loss group (Supporting Information Fig. S4), which was consistent with previous work demonstrating that 40% of MLH1 ‐methylated CRCs had BRAF V600E mutations . To date, widely accepted international standards for LS screening recommend no further genetic testing upon detection of MLH1 promoter methylation .…”

“…S4), which was consistent with previous work demonstrating that 40% of MLH1-methylated CRCs had BRAF V600E mutations. 26 To date, widely accepted international standards for LS screening recommend no further genetic testing upon detection of MLH1 promoter methylation. 13,27 However, it is noteworthy that three of 82 (3.7%) cases of CRC with somatic MLH1 promoter methylation were diagnosed as LS with a germline MLH1 mutation in our study, a result in line with previous studies.…”

TRK Fusions Are Enriched in Cancers with Uncommon Histologies and the Absence of Canonical Driver Mutations

“…To further interrogate the genomic context in which TRK fusions arise, the TMB of TRK fusionpositive and negative cases were compared. The acquisition of kinase fusions including TRK has been previously associated with the presence of MSI in colorectal cancers 27,28 . Indeed, of cases where MSI testing was available, 86% (6/7) of TRK fusion-positive colorectal cancers were microsatellite high (MSI-H).…”

DNA Mismatch Repair Deficiency Detection in Colorectal Cancer by a New Microsatellite Instability Analysis System

“…MSI-L phenotypes also occurred in higher percentage in stage I and II cancers in Table 3. In addition, germline sequencing was conducted on nine cases who were confirmed as Lynch syndrome positive [16]. All Lynch syndrome cases exhibited MMR protein expression loss by IHC and MSI-H by ProDx® MSI test.…”