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CANCER |
1 Department of Surgery, University of Western Australia, Nedlands 6907, Australia
2 Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands 6009, Australia
3 Department of Radiation Oncology, University of California, LA, USA
Correspondence to:
Correspondence to:
Dr B Iacopetta, Department of Surgery, University of Western Australia, Nedlands 6907, Australia;
bjiac{at}cyllene.uwa.edu.au
Background and aims: 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.
Keywords: colorectal cancer; CpG island methylator phenotype; hypermethylation
Abbreviations: CRC, colorectal cancer; MSI, microsatellite instability; CIMP+, CpG island methylator phenotype; MTHFR, methylenetetrahydrofolate reductase; PCR, polymerase chain reaction; MSP, methylation sensitive PCR; SSCP, single strand conformation polymorphism; 5-FU, 5-fluorouracil
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