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.

BackgroundTraditionally, it was believed that chronic rhinosinusitis with nasal polyps (CRSwNP) demonstrated less eosinophilic and more neutrophilic inflammation in China compared to North America and Europe. However, inflammatory patterns may change over time. The study aimed to analyze the changing trends in the clinical and histological characteristics of CRSwNP over time in China.MethodsA total of 115 consecutive CRSwNP patients from 2003 to 2005 and 114 consecutive CRSwNP patients from 2014 to 2016 were enrolled in this retrospective study. The clinical and histological data were compared between patients from the 2 time periods.ResultsThe percentage of eosinophils in nasal polyp tissue increased, and the percentage of neutrophils and total inflammatory cell count decreased, over 11 years. The proportion of eosinophilic CRSwNP significantly increased from 59.1% to 73.7% over 11 years. The proportion of neutrophils and the total inflammatory cell count in nasal polyps decreased, and the proportion of eosinophilic CRSwNP patients using intranasal corticosteroids 1 month before surgery increased remarkably over 11 years. Moreover, eosinophilic CRSwNP patients had better compliance with intranasal corticosteroid use than non‐eosinophilic CRSwNP patients, and patients with comorbid allergic rhinitis and asthma had better compliance with intranasal corticosteroid use than patients without those conditions.ConclusionEosinophilic CRSwNP, which was previously a minor subtype in East Asians, has increased remarkably in incidence to become the predominant CRSwNP subtype in Beijing, China, indicating that rhinologists should place greater emphasis on its diagnosis and treatment.

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