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

• Main Authors: Pi-Yueh Chang, Shih-Cheng Chang, Mei-Chia Wang, Jinn-Shiun Chen, Wen-Sy Tsai, Jeng-Fu You, Chia-Chun Chen, Hsiu-Ling Liu, Jy-Ming Chiang
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: Cancers
• Subjects: early onset; colorectal cancer; cancer susceptibility gene; germline mutation; polyp; normal control
• Online Access: https://www.mdpi.com/2072-6694/12/12/3560

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 (<i>MLH1, BRCA1, BRCA2, CHEK2, BLM, </i>and <i>NTHL1</i>) were detected in nine participants. One frameshift mutation in <i>BRCA2</i> and one frameshift mutation in the <i>CHEK2</i> gene were found in a normal control and two colorectal polyp patients, respectively. One young sporadic CRC patient carried two heterozygous mutations, one in <i>MLH1</i> and one in <i>BRCA1</i>. 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.