Caffeine phenotyping in patients with familial adenomatous polyposis may shed light on sporadic colon cancer and acetylator status.

EDITOR,-The age at which patients with familial adenomatous polyposis (FAP) develop colorectal cancer (CRC) is variable, as is the development of extracolonic tumours in the syndrome. This could be due to the effect of different mutations in the responsible gene,l environmental factors or the influence of risk modifier genes. Enzymes that metabolise dietary carcinogens such as N-acetyltransferase2 (NAT2) and cytochrome P450 CYP1A2 are potential modifier genes and fast metabolisers for NAT2 and CYP1A2 have been reported to be at greater risk of sporadic CRC.2 In addition bile from FAP patients has been found to contain higher concentrations of carcinogens3 than that from controls. Therefore, Spigelman et al (Gut 1995; 36: 251-4) have examined the frequency ofphenotypes for NAT2 and CYP1A2 in FAP against controls and also examined the influence of colectomy on the caffeine metabolite ratios used for phenotyping. We believe that a reexamination of their data questions the use of the phenotyping method for NAT2 in these patients and may help to explain the excess risk for fast acetylators seen in phenotyping studies of colorectal cancer. NAT2 has a well characterised polymorphism4 and patients can be classified as fast or slow acetylators either by means of phenotyping, using a probe drug such as caffeine, or by genotyping using a simple PCR based assay for the four common alleles. In healthy young subjects the two methods are well correlated.4 In their paper Spigelman et al state that there is no significant difference in the value of the metabolic ratio for NAT2 phenotype in a group of six patients before and after surgery. However, if we re-examine the data from Fig 2 and look at the apparent phenotype in each subject rather than the metabolic ratio it would seem that one subject had changed from a slow to a fast acetylator after colectomy, one has done the reverse, and another who seems very close to the cut off point of 0-48 before surgery is now clearly a fast acetylator. Thus possibly as many as 50% of subjects seem to have changed their phenotype in this small group of subjects. If this finding were repeated in a larger sample it would invalidate the conclusion that there are more slow acetylators in the FAP group. While fast acetylator status has been associated with greater risk for sporadic CRC in a number of phenotyping studies in white subjects,2 two genotyping studies in Japanese subjects found no increased risk.5 6 It may be that this is due to different dietary risk factors or the high (90%) prevalence of fast acetylators in Japan but clearly it could also result from a disease effect on the phenotyping procedure causing misclassification of patients in the phenotyping studies in white subjects. We believe that phenotyping may be inaccurate in people with concurrent diseases and that the study by Spigelman et al gives some support tO this theory. In contrast, genotyping offers a quick and simple means of assessing acetylator status, which is unaffected by concurrent illness or drugs. Until further studies have validated phenotyping in patients with FAP or CRC we believe that genotyping is the method of choice for NAT2 analysis and a genotyping study is required to establish whether fast acetylator status is truly a risk factor for this disease in white subjects.