Journal Article

A High Degree of LINE-1 Hypomethylation Is a Unique Feature of Early-Onset Colorectal Cancer

Shia, Jinru, Takahashi, Masanobu, Castells, Antoni, Shen, Yan, Hur, Keun, Moreira, Leticia, Boland, C. Richard, Giraldez, Maria Dolores, Cabanne, Ana, Barugel, Mario Edmundo, Arnold, Mildred, Jover, Rodrigo, Castellvi-Bel, Sergi, Balaguer, Francesc, Cuatrecasas, Miriam, Antelo, Marina, Roca, Enrique Luis, Bujanda, Luis, Llor, Xavier, Goel, Ajay, Andreu, Montserrat

2012

Overview

Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that is often associated with a poor prognosis. Methylation levels of genomic repeats such as LINE-1 elements have been recognized as independent factors for increased cancer-related mortality. The methylation status of LINE-1 elements in early-onset CRC has not been analyzed previously. We analyzed 343 CRC tissues and 32 normal colonic mucosa samples, including 2 independent cohorts of CRC diagnosed ≤ 50 years old (n=188), a group of sporadic CRC >50 years (MSS n=89; MSI n=46), and a group of Lynch syndrome CRCs (n=20). Tumor mismatch repair protein expression, microsatellite instability status, LINE-1 and MLH1 methylation, somatic BRAF V600E mutation, and germline MUTYH mutations were evaluated. Mean LINE-1 methylation levels (± SD) in the five study groups were early-onset CRC, 56.6% (8.6); sporadic MSI, 67.1% (5.5); sporadic MSS, 65.1% (6.3); Lynch syndrome, 66.3% (4.5) and normal mucosa, 76.5% (1.5). Early-onset CRC had significantly lower LINE-1 methylation than any other group (p<0.0001). Compared to patients with <65% LINE-1 methylation in tumors, those with ≥ 65% LINE-1 methylation had significantly better overall survival (p=0.026, log rank test). LINE-1 hypomethylation constitutes a potentially important feature of early-onset CRC, and suggests a distinct molecular subtype. Further studies are needed to assess the potential of LINE-1 methylation status as a prognostic biomarker for young people with CRC.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptor Proteins, Signal Transducing - genetics / Adenoma - epidemiology / Adenoma - genetics / Adenoma - metabolism / Adenoma - mortality / Adult / Age / Age of Onset / Analysis / Argentina - epidemiology / Bioindicators / Biomarkers / Cancer / Case-Control Studies / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - epidemiology / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - mortality / Colorectal Neoplasms, Hereditary Nonpolyposis - epidemiology / Colorectal Neoplasms, Hereditary Nonpolyposis - genetics / Colorectal Neoplasms, Hereditary Nonpolyposis - metabolism / Colorectal Neoplasms, Hereditary Nonpolyposis - mortality / Càncer / Càncer colorectal / Deoxyribonucleic acid / DNA / DNA Glycosylases - genetics / DNA Methylation / DNA-Binding Proteins - genetics / Epidemiologia genètica / Epigenetics / Female / Gastroenterology / Gene Expression / Genetic aspects / Genetic disorders / Genetic epidemiology / Germ-Line Mutation / Health aspects / Humans / Internal medicine / Long Interspersed Nucleotide Elements / Male / Medical diagnosis / Medicine / Methylation / Microsatellite Instability / Middle Aged / Mismatch repair / MLH1 protein / Mucosa / Mutation / MutL Protein Homolog 1 / MutS Homolog 3 Protein / Nuclear Proteins - genetics / Oncology / Pathology / Physiological aspects / Prognosis / Proto-Oncogene Proteins B-raf - genetics / Spain - epidemiology / Stability / Survival Analysis / Tissues / Tumors / United States - epidemiology / Young adults