Universal Molecular Screening And Clinicopathologic Characteristics Of Lynch Syndrome Related Colorectal Cancer

Background:Lynch syndrome(LS)is the most common colorectal cancer(CRC)and its related carcinomas detected by DNA mismatch repair(MMR)genes and EPCAM gene mutations.LS is autosomal dominant,and its' molecular detection shows microsatellite instability(MSI)and/or loss of mismatch repair proteins(MMR).Because of lacking of the clinical phenotype of typical adenomatous polyps,it is also called hereditary nonpolyposis colorectal cancer(HNPCC).Among patients with MMR-deficient CRC,about 50%patients didn't carry the MLH1 promoter methylation and/or pathogenic DNA MMR genes and EPCAM gene,which are termed "Lynch-like syndrome"(LLS).Although LS accounts for a small proportion of all CRCs,patients and their families have a higher risk of lifetime cancer,an earlier age of onset,and a faster rate of cancerization.It is crucial to make screening and intervention measures for such patients.The current methods for screening LS and LLS include family history,microsatellite detection,immunohistochemical(IHC),next generation sequencing(NGS)and so on,but there haven't been optimal diagnosed and screening methods for LS.LLS patient are considered to have a risk of developing CRC,but the pathogenesis is unclear.So far,there hasn't been any consensus on treatments and screening strategies for patients with LLS.There have been no reports about LLS in China currently.Therefore,it is of great significance to strengthen the collection of family genetic samples and clinical pathological molecular information of patients with LS and LLS.Aim:In this study,we analyzed a large and well-annotated cohort of CRC patients to assess the proportion and related clinicopathologic characteristics of LS and LLS through the universal molecular testing strategies(1HC,microsatellite detection,BRAF V600E testing,MLH1 promoter methylation,NGS).Methods:Patients with colorectal cancer who underwent surgical resection from 2014 to 2018 in our institution were included.Clinicopathologic and molecular features were collected from archives,including age at diagnosis,sex,tumor location,tumor size,tumor morphology,histological differentiation and type,serosa infiltration,vascular tumor emboli,nerve invasion,tumor deposit(TD),lymph nodes and stage at diagnosis(TNM).Immunohistochemical for MMR proteins expression,microsatellite instability status and BRAF V600E mutation were evaluated.Tumors with deficiency of MMR proteins and/or MSI were sent for NGS.Patients without MMR genes and EPCAM gene mutation were sent for MLH1 methylation analysis.Fisher exact test,Chi-Square test and Kruskal-Wallis test are used to analyze the comparison between different groups for quantitative variables.Results:A total of 404 patients were included.Loss of expression of MMR proteins was identified in 35 patients(8.7%).MSI-H,MSS were observed in 28(6.9%)and 376(93.1%)patients respectively.BRAF V600E mutation was detected in 13 patients(3.2%).Among the 42 patients with MMRd,7 patients(7/42,16.7%)were confirmed with MMR germline mutations and 7 patients(7/42,16.7%)with MLH1 methylation.While 28 patients(28/42,66.7%)had no pathogenic mutations in MMR genes,EPCAM,BRAF or MLH1 methylation,which were considered to be LLS.Most of patients with loss of MMR proteins but MSS were LLS(13/14,92.9%).The average age of LS was 44.7(SD11.1)years,which was significantly younger than that of LLS(60.7±11.6)and SCRC(70.0±14.8).LS is more common in the left colon(57.1%,4/7)and right colon(42.9%,3/7),while LLS is more common in left colon(64.3%,18/28),especially in rectal cancer(39.3%,11/28);SCRC tumors mainly occurred in the proximal colon(85.7%,6/7).Lymph nodes metastasis occurred in 50%of patients with LLS(14/28 N2),which was significantly higher than LS and SCRC(28.6%,2/7 N1 and 14.3%,1/7 N1).Conclusion:In this study,the proportion of LS was 1.7%.We confirmed that the majority of LS are attributable to MSI-H.66.7%of patients with deficiency of MMR proteins and/or MSI were classified as LLS,which were significantly higher than reports of western countries.Tumors with LLS were more likely to locate in left-side colon,especially rectum,and carry lymph node metastases.Further researches are needed to adopt to explore the etiological factors and molecular mechanism of LLS.