Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands.
OBJECTIVE
A subgroup of colorectal cancers (CRC) referred to as the CpG island methylator phenotype (CIMP+) shows simultaneous methylation of multiple CpG islands. The clinicopathological and molecular characteristics of this phenotype remain uncertain however.


METHODS
We analysed methylation of CpG islands in the p16 and MDR1 genes and MINT-2 clone in 275 stage II/III CRCs.


RESULTS
Concurrent methylation of two or more CpG islands was observed in 32% of cases and was considered to represent CIMP+. These were often poorly differentiated, had less TP53 mutations, and originated frequently in the proximal or higher stage CRC compared with CIMP- tumours (p<0.05 for each). CIMP+ had no prognostic significance in stage II or stage III CRC treated by surgery alone. hMLH1 methylated tumours comprised the majority (81%) of cases with microsatellite instability, were frequently observed in older female patients, were often poorly differentiated or CIMP+, and contained wild-type K-ras (p<0.05 for each). Females who were heterozygous or homozygous for the C677T MTHFR polymorphism were at increased risk of developing CIMP+ CRC (odds ratio 2.17, 95% confidence interval 1.03-4.57; p=0.037).


CONCLUSIONS
These observations made in a relatively large unselected series of CRC support the notion that CIMP+ characterises a subgroup of tumours with distinctive phenotypic features.
van Rijnsoever
M
M
Department of Surgery, University of Western Australia, Nedlands 6907, Australia.
Grieu
F
F
Elsaleh
H
H
Joseph
D
D
Iacopetta
B
B
D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D019450:Genes, MDR; D019942:Genes, p16; D011905:Genes, ras; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D010641:Phenotype; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012306:Risk; D015996:Survival Rate