A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer.

Abstract

OBJECTIVE:

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.

DESIGN:

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.

RESULTS:

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).

CONCLUSIONS:

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.

• Authors: Marina Antelo, Francesc Balaguer, Jinru Shia, Yan Shen, Keun Hur, Leticia Moreira, Miriam Cuatrecasas, Luis Bujanda, Maria Dolores Giraldez, Masanobu Takahashi, Ana Cabanne, Mario Edmundo Barugel, Mildred Arnold, Enrique Luis Roca, Montserrat Andreu, Sergi Castellvi-Bel, Xavier Llor, Rodrigo Jover, Antoni Castells, C Richard Boland, Ajay Goel
• Journal: PloS one (PLoS One) Vol. 7 Issue 9 Pg. e45357 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23049789 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• DNA-Binding Proteins
• MLH1 protein, human
• MSH3 protein, human
• MutS Homolog 3 Protein
• Nuclear Proteins
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• DNA Glycosylases
• mutY adenine glycosylase
• MutL Protein Homolog 1

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adenoma (epidemiology, genetics, metabolism, mortality)
• Adult
• Age of Onset
• Argentina (epidemiology)
• Case-Control Studies
• Colorectal Neoplasms (epidemiology, genetics, metabolism, mortality)
• Colorectal Neoplasms, Hereditary Nonpolyposis (epidemiology, genetics, metabolism, mortality)
• DNA Glycosylases (genetics)
• DNA Methylation
• DNA-Binding Proteins (genetics)
• Female
• Gene Expression
• Germ-Line Mutation
• Humans
• Long Interspersed Nucleotide Elements
• Male
• Microsatellite Instability
• Middle Aged
• MutL Protein Homolog 1
• MutS Homolog 3 Protein
• Nuclear Proteins (genetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Spain (epidemiology)
• Survival Analysis
• United States (epidemiology)