Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers.
BACKGROUND
Multiple epigenetic and genetic changes have been reported in colorectal tumors, but few of these have clinical impact. This study aims to pinpoint epigenetic markers that can discriminate between non-malignant and malignant tissue from the large bowel, i.e. markers with diagnostic potential. The methylation status of eleven genes (ADAMTS1, CDKN2A, CRABP1, HOXA9, MAL, MGMT, MLH1, NR3C1, PTEN, RUNX3, and SCGB3A1) was determined in 154 tissue samples including normal mucosa, adenomas, and carcinomas of the colorectum. The gene-specific and widespread methylation status among the carcinomas was related to patient gender and age, and microsatellite instability status. Possible CIMP tumors were identified by comparing the methylation profile with microsatellite instability (MSI), BRAF-, KRAS-, and TP53 mutation status.


RESULTS
The mean number of methylated genes per sample was 0.4 in normal colon mucosa from tumor-free individuals, 1.2 in mucosa from cancerous bowels, 2.2 in adenomas, and 3.9 in carcinomas. Widespread methylation was found in both adenomas and carcinomas. The promoters of ADAMTS1, MAL, and MGMT were frequently methylated in benign samples as well as in malignant tumors, independent of microsatellite instability. In contrast, normal mucosa samples taken from bowels without tumor were rarely methylated for the same genes. Hypermethylated CRABP1, MLH1, NR3C1, RUNX3, and SCGB3A1 were shown to be identifiers of carcinomas with microsatellite instability. In agreement with the CIMP concept, MSI and mutated BRAF were associated with samples harboring hypermethylation of several target genes.


CONCLUSIONS
Methylated ADAMTS1, MGMT, and MAL are suitable as markers for early tumor detection.
Ahlquist
Terje
T
Department of Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway. terje.c.ahlquist@rr-research.no
Lind
Guro E
GE
Costa
Vera L
VL
Meling
Gunn I
GI
Vatn
Morten
M
Hoff
Geir S
GS
Rognum
Torleiv O
TO
Skotheim
Rolf I
RI
Thiis-Evensen
Espen
E
Lothe
Ragnhild A
RA
D000236:Adenoma / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D016000:Cluster Analysis; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D055088:Early Detection of Cancer; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012727:Sex Characteristics
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm