Pathogenic Germline Mutations of DNA Repair Pathway Components in Early-Onset Sporadic Colorectal Polyp and Cancer Patients

Cancers

Jeng-Fu You¹  Jy-Ming Chiang¹  Wen-Sy Tsai¹  Jinn-Shiun Chen¹  Mei-Chia Wang²  Hsiu-Ling Liu²  Pi-Yueh Chang²  Shih-Cheng Chang²  Chia-Chun Chen³ 

[1] Department of Colorectal Surgery, Chang Gung Memorial Hospital, No. 5 Fu-Shing St. Kweishan, Taoyuan 33305, Taiwan;Department of Laboratory Medicine, Chang Gung Memorial Hospital, No. 5 Fu-Shing St. Kweishan, Taoyuan 33305, Taiwan;Molecular Medicine Research Center, Chang Gung University, No. 259, Wenhua 1st Rd., Kweishan, Taoyuan 33302, Taiwan;

关键词: early onset;    colorectal cancer;    cancer susceptibility gene;    germline mutation;    polyp;    normal control;   

DOI  :  10.3390/cancers12123560

来源: DOAJ

【 摘 要 】

Given recent increases in the proportion of early-onset colorectal cancer (CRC), researchers are urgently working to establish a multi-gene screening test for both inherited and sporadic cancer-susceptible individuals. However, the incidence and spectrum of germline mutations in young sporadic CRC patients in East Asian countries and, especially, in sporadic polyp carriers and normal individuals are unknown. Peripheral blood samples were collected from 43 colonoscopy-proved normal controls and from 50 polyp patients and 49 CRC patients with no self-reported family history of cancer. All participants were under 50 years old. Next-generation sequencing with a panel of 30 CRC-associated susceptibility genes was employed to detect pathogenic germline mutations. The germline mutation carrier rates were 2.3%, 4.0%, and 12.2% in the normal, polyp, and cancer groups, respectively. A total of seven different mutations in six DNA repair pathway-related genes (MLH1, BRCA1, BRCA2, CHEK2, BLM, and NTHL1) were detected in nine participants. One frameshift mutation in BRCA2 and one frameshift mutation in the CHEK2 gene were found in a normal control and two colorectal polyp patients, respectively. One young sporadic CRC patient carried two heterozygous mutations, one in MLH1 and one in BRCA1. Three mutations (MLH1 p.Arg265Cys, MLH1 p.Tyr343Ter and CHEK2 p.Ile158TyrfsTer10) were each found in two independent patients and were considered “founder” mutations. This is the first report to demonstrate high percentage of germline mutations in young sporadic colorectal polyp, CRC, and general populations. A multi-gene screening test is warranted for the proactive identification of cancer-predisposed individuals.

【 授权许可】

Unknown