TY - JOUR
T1 - A High Degree of LINE-1 Hypomethylation Is a Unique Feature of Early-Onset Colorectal Cancer
AU - Antelo, Marina
AU - Balaguer, Francesc
AU - Shia, Jinru
AU - Shen, Yan
AU - Hur, Keun
AU - Moreira, Leticia
AU - Cuatrecasas, Miriam
AU - Bujanda, Luis
AU - Giraldez, Maria Dolores
AU - Takahashi, Masanobu
AU - Cabanne, Ana
AU - Barugel, Mario Edmundo
AU - Arnold, Mildred
AU - Roca, Enrique Luis
AU - Andreu, Montserrat
AU - Castellvi-Bel, Sergi
AU - Llor, Xavier
AU - Jover, Rodrigo
AU - Castells, Antoni
AU - Boland, C. Richard
AU - Goel, Ajay
PY - 2012/9/25
Y1 - 2012/9/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866707635&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0045357
DO - 10.1371/journal.pone.0045357
M3 - Article
C2 - 23049789
AN - SCOPUS:84866707635
SN - 1932-6203
VL - 7
JO - PLoS ONE
JF - PLoS ONE
IS - 9
M1 - e45357
ER -
