Germline Mutations In Patients With Multiple Colorectal Polyps And Hereditary Colorectal Cancer Syndromes

Background and Aim: Approximately 30% of CRC patients display a complex inheritance pattern,and 5–10% of CRC cases have been shown to be hereditary.Multiple colorectal polyps are relevant in hereditary colorectal cancer(CRC)syndromes,which are thought to be caused by multiple events including germline mutations.Previous studies showed that most of the adenoma polyps are caused by APC/Wnt pathways.Familial adenomatous polyposis(FAP)which accounts for about 1-2% of all colorectal cancer are caused by the APC and MUTYH gene pathogenic germline mutations.The majority of the patients with FAP show hundreds of adenomatous polyps in their colorectum.Lynch syndrome(LS),also known as hereditary non-polyposis colorectal cancer(HNPCC),which accounts for about 5-7% of all colorectal cancer are caused by mismatch repair(MMR)gene pathogenic germline mutations.Some of the patients with LS show multiple colorectal adenoma polyps too.And what's more,the patients with Peutz-Jeghers syndrome(PJS)show multiple colorectal hamartomatous polyps.About 50% of the patients with PJS are the carriers of STK11 gene pathogenic germline mutations.This studywas aimed to characterize germline mutations in Chinese patients with multiple colorectal polyps including adenoma and hamartomatous polyps,and summary the genetic testing strategy about the high-risk groups of hereditary CRC syndromes.Methods: Patients with >10 colorectal polyps including adenoma and hamartomatous polyps at the Department of Gastroenterology of the PLA Army General Hospital were enrolled from January 2014 to December 2015.These patients were divided into the high,moderate,and mild-risk groups according to the risk of hereditary colorectal cancer.White blood cell samples were collected and DNA was extracted to sequence a panel of 19 genes previously associated with CRC by next-generation sequencing.Results: A total of 96 patients were enrolled in the study.Pathogenic germline mutations were found in 24(24/33,72.73%),nine(9/24,37.5%),and three patients(3/39,7.7%)in the high-,moderate-,and mild-risk groups,respectively.Based on the results above,we suggested a strategy about gene sequencing test for the patients with multiple polyps,and the sensitivity and specificity of the screening strategy were 97% and 57%,respectively.Otherwise,four of eight patients with MUTYH pathogenic germline mutations had the c.A934-2G monoallelic germline mutation,whereas three of eight patients had the C55 T MUTYH germline mutation.Concurrent pathogenic germline mutations in APC and MUTYH were also observed.Conclusions: The patients with 10–20 polyps and a personal or family history of CRC,as well as those with more than 20 polyps should undergo a gene sequencing test.A genetic screening strategy comprising 19 genes was effective to screen for hereditary CRC syndromes in patients with multiple colorectal polyps.The MUTYH germline mutation hotspots in Chinese patients may be different from those in Caucasian patients.