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

ANTELO, M.; BALAGUER, F.; SHIA, J.; SHEN, Y.; HUR, K.; MOREIRA, L.; CUATRECASAS, M.; BUJANDA, L.; GIRALDEZ, MD.; TAKAHASHI, M.; CABANNE, A.; BARUGEL, M; ARNOLD, M.; ROCA, E.; ANDREU, M.; CASTELLVI-BELL, S.; LLOR, X.; JOVER, R.; CASTELLS, A.; BOLAND, R.; GOEL, A.

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2012 vol. 7 p. 1 - 12

1932-6203

Objective: Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that is often associated with a por 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 before 50 years old (n = 188), a group of sporadic CRC .50 years (MSS n = 89; MSI n = 46), and a group of Lynchs yndrome 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 (6SD) 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 less than 65% LINE-1 methylation in tumors, those with more than 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.