Identification of new cases of early-onset colorectal cancer with an MLH1 epimutation in an ethnically diverse South African cohort

• Published in: Clinical genetics Vol. 80; no. 5; pp. 428 - 434
• Main Authors: Hitchins, MP, Owens, SE, Kwok, C-T, Godsmark, G, Algar, UF, Ramesar, RS
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-2011; Wiley-Blackwell
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; Age; Biological and medical sciences; Colorectal cancer; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; DNA Methylation; DNA Mismatch Repair - genetics; Endometrium; epimutation; Ethnic Groups; Female; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene silencing; General aspects. Genetic counseling; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Humans; Leukocytes; Lynch syndrome; Male; Medical genetics; Medical sciences; Microsatellites; Middle Aged; Minority & ethnic groups; mismatch repair; MLH1; MLH1 protein; Molecular and cellular biology; Mosaicism; Mosaics; MSH2 protein; MSH6 protein; Mutation; MutL Protein Homolog 1; Nuclear Proteins - genetics; South Africa; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; South Africa; Africa; Human; epimutation; Hereditary nonpolyposis colorectal cancer; Rectal disease; Colorectal cancer; Identification; Malignant tumor; MLH1; Genetic disease; Colonic disease; Case study; Cohort study; Epigenetics; Digestive diseases; Intestinal disease; Genetics; Early; Cancer; Lynch syndrome
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2011.01660.x

Hitchins MP, Owens SE, Kwok C‐T, Godsmark G, Algar UF, Ramesar RS. Identification of new cases of early‐onset colorectal cancer with an MLH1 epimutation in an ethnically diverse South African cohort.
Lynch syndrome, characterized by young‐onset microsatellite unstable colorectal, endometrial and other cancers, is caused by germline mutations of the mismatch repair genes, most commonly MLH1, MSH2 and MSH6. Constitutional MLH1 epimutations, which manifest as soma‐wide methylation and transcriptional silencing of a single allele, have been identified in a subset of patients with a Lynch syndrome phenotype in the absence of a mismatch repair mutation. This study aimed to determine if MLH1 epimutations predispose to the development of young‐onset colorectal cancer in an ethnically diverse population of South African subjects. A total of 122 index cases with a diagnosis of colorectal cancer below 50 years of age, who had tested negative for a definitive pathogenic mutation of the key mismatch repair genes, were screened for constitutional MLH1 methylation in their leukocyte DNA. Monoallelic MLH1 epimutations were identified in two sporadic cases (1.6%): a male of black African descent and an Asian Indian female. Few alleles were affected by methylation in the female, indicating mosaicism. These cases provide further evidence of the aetiological role for MLH1 epimutations in cancer development and the requirement for sensitive molecular screening techniques to identify mosaic epimutations. Furthermore, while this mechanism is rare, it affects patients of multiple ethnic origins.