A Modified Screening Strategy For Lynch Syndrome Among MLH1-Deficient CRCs And Genetic Testing Of Lynch Syndrome In China:Survey Of Pathologists Practice Pattern And Patients' Knowledge And Willingness

Background:The diagnostic role of BRAF mutation testing and MLH1 methylation analysis in distinguishing LS and sporadic CRC with MLH1-deficiency in Chinese population is unclear.It has been reported that BRAF V600E mutation rate in Asian CRC patients is much lower than that observed in Western countries,therefore there is a concern about the efficacy of BRAF mutation analysis in Lynch syndrome(LS)screening.The aim of this study was to compare the utility of BRAF V600E mutation with MLH1 promoter methylation analysisfor identifying patients with MLH1-deficient CRC for germlinemutation testing inChinese population.Patients and Methods:A total of 169 patients with MLH1-deficient CRC from 4104 consecutive CRC patients were analyzed.The MLH1 methylation status was evaluated by methylation-specific PCR,and the BRAF mutation status was assessed by real-time PCR.Germline mutation testing was performed in patients with both BRAF wild-typeand MLH1 promotermethylation.Results:BRAF mutation was found in only 17.2%(29/169)of patients.In contrast,52.9%(89/169)of patients displayed MLH1 promotermethylation.Among 61 patients(36.1%,61/169)who were BRAF V600E wild-typeand presenting MLH1 promotermethylation,germline mutations of MLH1 gene were also detected in 6 patients.All these 6 patients had a CRC family history in at least 1 first-degree or second-degree relative.The other 6 patients with CRC family history did not show germline mutations.Thecombination ofMLHl promotor methylation analysis and family history of CRCs could preclude significantly more patients from germline mutation test than BRAF mutation test(54.5%vs.82.8%,P<0.001).Conclusion:Thecombination ofMLH1 promoter methylation analysis and family history of CRCs showed better performance than BRAF mutation analysis alone in a selection of patients for germline mutation testing in Chinese population.Objective : The principal objective of this study was to investigate the universal screening behavior of Lynch syndrome of colorectal cancers(CRCs)in domestic hospitals and assess the knowledge and willingness of genetic counseling and testing in CRC patients with mismatch repair(MMR)protein deficiency or their relatives.Methods: In the first part,we conducted a survey of pathologists from 91 hospitals.The survey instrument investigated the name and level of hospitals,professional title and education background of interviewees.Screening activities of MMR expression in colorectal cancer patients as well as introduction and notification of genetic testing for Lynch syndrome were also assessed.In the second part,323 patients who had undergone surgery for CRCs and were diagnosed as MMR deficiency(dMMR)between December2011 and December 2014 in Chinese National Cancer Center were reviwed.The knowledge and willingness of genetic counseling and testing of hereditary tumors such as Lynch syndrome in CRCs patients or their relatives were investigated through telephones.Results: The MMR expression could be tested in 51.6% investigated hospitals and 37.5%rank 3 hospitals and 50% cancer hospitals conducted this test on CRC patients routinely,however few rank 2 hospitals developed such detection.Unfortunately,the reminder of the necessity of “genetic testing for Lynch” were uncommonly seen on pathological reports of patients with dMMR.A total of 219 patients with dMMR or tlieir relatives participated in our investigation.Most of the respondents were unaware of genetic counselingand genetic testing.However,after a brief introduction,72.2% of them were wilingto accept genetic testing.27.9% interviewees still recused to do genetic testing for the fear of adverse effects of genetic test,worry about expense and denial of hereditary possibilities.Most patients had unsatisfactory compliance of colonoscopic surveillance.Conclusions : Most hospitals have not developed universal screening of Lynch syndrome in CRCs.Most respondents were xinaware of hereditary tumors? but had apparent willingness to accept them.Misunderstandingof genetic characteristics,costsand concemingabout discrimination are obstacles for the respondents to accept genetic counseling,genetic testingand related screening prevention.