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


METHODS
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.
Oncology and Pathology Sections, Hospital of Gastroenterology "Dr. C. B. Udaondo", Buenos Aires, Argentina.
Marina
M
Antelo
Francesc
F
Balaguer
Jinru
J
Shia
Yan
Y
Shen
Keun
K
Hur
Leticia
L
Moreira
Miriam
M
Cuatrecasas
Luis
L
Bujanda
Maria Dolores
MD
Giraldez
Masanobu
M
Takahashi
Ana
A
Cabanne
Mario Edmundo
ME
Barugel
Mildred
M
Arnold
Enrique Luis
EL
Roca
Montserrat
M
Andreu
Sergi
S
Castellvi-Bel
Xavier
X
Llor
Rodrigo
R
Jover
Antoni
A
Castells
C Richard
CR
Boland
Ajay
A
Goel
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000236:Adenoma / Q000453:epidemiology* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D000328:Adult; D017668:Age of Onset; D001118:Argentina / Q000453:epidemiology; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D045647:DNA Glycosylases / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D018095:Germ-Line Mutation; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013030:Spain / Q000453:epidemiology; D016019:Survival Analysis; D014481:United States / Q000453:epidemiology
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D000070957:MutL Protein Homolog 1