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In their interesting review of colorectal cancer (CRC) as a model for epigenetic tumourigenesis, Wong, et al (in this issue, p 139) discuss the role of hereditary factors in explaining the aetiology of CRC with DNA methylation. Firstly, they assert that larger studies do not support a hereditary aetiology for the CpG island methylator phenotype (CIMP). Secondly, they suggest that MLH1 epimutation (or germline hemi-allelic methylation) may be heritable. Both of these propositions may be challenged.
In the case of an inherited predisposition to CRCs with acquired DNA methylation or CIMP, a family cancer clinic-based study that excluded families with the Lynch syndrome, found that members with CRCs showing the CIMP had a 13-fold increased risk of having a first-degree relative with cancer (not necessarily CRC) as compared with those without CIMP-positive CRC.1 A hospital-based study by Ward et al2 could not confirm this finding, but it is pertinent that they excluded families considered to have hereditary nonpolyposis colorectal cancer (HNPCC). Ward et al regularly use clinical definitions for HNPCC.3 The exclusion of “HNPCC” families is likely to have introduced a major bias, as not all families meeting a clinical definition for HNPCC (eg, the Amsterdam criteria) in fact show evidence of DNA mismatch repair deficiency that would be indicative of a germline defect in a DNA mismatch repair gene.4
The second large study cited by Wong et al5 was a population-based series that assessed CIMP in 864 CRCs and defined CIMP-high as …