The Pedigree Analysis Of A Typical Lynch Syndrome Family

Objective:Lynch syndrome is one of the most common hereditary colorectal cancer.Nowadays,the diagnosis of Lynch syndrome mainly rely on the IHC and MSI test for patients who meet the Amsterdam criteria or Bethesda Guidelines.However,the missed diagnoses and misdiagnoses still cannot be totally avoided when using these methods.In this case,we trace a typical proband and the family found:in clinical practice which meet the Amsterdam II critieria and conducted the IHC/MSI tests and the next-generation gene sequencing of hereditary colorectal cancer related genes for the proband to locate the mutation.Meanwhile,we evaluate the consensus of these methods and provide genetic consulting for all family members after the confirmatory experiments about pathogenic mutation.We expect to improve the protocols in clinical diagnosis and family management of Lynch syndrome.Methods:We detected a patient met the Amsterdam II standards during clinical work and did CT scan,barium enema examination of colon and coloscopy to evaluate the patient's disease and then performed subtotal colectomy and got the specimen to do IHC examination for the 4 protein products of the MMR genes and the microsatellite examination to estimate whether it is stable or not..The family tree is charted as soon as we got the complete family history.We conducted the targeted next generation sequencing to confirm the details of gene mutation of the patients in this family.Meanwhile the verifying test was done for rest of the family members to distinguish other mutation carriers to guide the later health consulting.Results:The CT scan and colonoscopy of the proband showed synchronous multi-primary colorectal cancer.The procedure of radical subtotal colectomy was conducted.The results of pathology examination showed well to moderately differentiated adenocarcinoma in both ascending and descending colon,partially mucinous.The IHC examination showed an absence of MSH2 and MSH6 proteins.The MSI examination showed MSI-H.The pedigree tree showed that there are 7 pathology-confirmed patients from 4 generations in this family.The cancer spectrum includes colorectal and endometrial carcinoma.The gene sequencing showed all the patients share a same pathogenic gene mutation in MSH2(c.2038C>T),which caused the absence of MSH2 protein.The confirmatory experiment detected 2 normal phenotype carriers,who were found multi-polyps in their colon in the later colonoscopy we suggested.Conclusion:The members in this family have suffered from multiple types of cancer for continuous 4 generations,which makes the family a typical Lynch syndrome family met the Amsterdam II criteria.The IHC/MSI examination results of the proband's pathological specimen is consistent with gene sequencing,which suggested the mutation in MSH2 gene.Gene sequencing is helpful with the screening in Lynch syndrome family and provides a solid evidence for the following genetic consulting and familial arrangement.