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 …