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From errant enzymes to colon cancers

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The suggestion that some colorectal cancers (CRCs) develop by a methylation pathway has been given support by a genetic study of 500 patients in Australia. The findings support the view that key enzymes in the metabolism of folate and methyl groups, which affect DNA methylation, influence predisposition to CRCs, particularly sporadic (non-familial) cancers with microsatellite instability (MSI).

The researchers hypothesised that genetic polymorphisms in enzymes of folate metabolism—methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS)—would respectively predispose to or protect against MSI+ CRCs, owing to their effects on enzyme activity.

Comparison of the frequency of polymorphic genotypes in patients with MSI+ and MSI− CRCs and in controls confirmed the hypothysis. The MTHFR TT genotype—which results in a 30% drop in enzyme activity—was significantly associated with CRC, but in patients aged ≥70 years, compared with age matched controls (12% v 7%). It also correlated with increased age at diagnosis of proximal tumours (median age 74 v 67 years) and was found almost twice as commonly in MSI + as in MSI− tumours (16% v 9%). The CBS844ins68 genotype—which increases activity in reducing plasma homocysteine—was less common in proximal tumours than in controls (4% v 10%).

The study was performed in 500 patients with CRC: 75 cancers were MSI+ cancers of the proximal colon and 426 were MSI− cancers of the proximal (203) or distal (233) colon. The controls were 1207 healthy subjects from the Western Australian population. A subgroup of 155 of the controls was typed for the CBS polymorphism.

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