Association of CYP2C9 genotypes leading to high enzyme activity and colorectal cancer risk

Carmen Martínez1, Elena García-Martín2, José M. Ladero3, Javier Sastre4, Francisco Garcia-Gamito5, Manuel Diaz-Rubio3 and José A.G. Agúndez1,,6

1 Department of Pharmacology, Medical School and
2 Department of Biochemistry, School of Biological Sciences, University of Extremadura, Avda. de Elvas s/n. E-06071, Badajoz, Spain,
3 Service of Gastroenterology and
4 Medical Oncology, San Carlos University Hospital, Prof. Martin Lagos s/n, E-28040, Madrid, Spain and
5 Service of Surgery, Hospital INSALUD, Pol Nueva Ciudad s/n E-06800 Mérida, Spain

Dear Sir,

Thank you for the opportunity to reply the letter from Yasar et al. In their letter, Yasar et al., expressed concerns regarding the selection of the control group in our previous study (1). With regard to the first matter addressed i.e., that patients with benign diseases of the colon are more adequate controls than healthy subjects we do not agree for the following reasons.

From a clinical point of view it has little sense to compare cancer patients with patients with benign diseases. According to the suggestion from Yasar et al., a control group could have been composed from individuals with benign polyps, ulcerative colitis and irritable bowel syndrome among the most prevalent benign diseases of the colon. However, colorectal polyps may be pre-cancerous and the risk to develop colorectal cancer is much higher in subjects with polyps than in the general population. In fact it has been reported that ~95% of colorectal cancers arise in benign adenomatous polyps (2). This makes this subgroup inadequate for comparison.

Ulcerative colitis is a disease of unknown aetiology. A role for the influence of xenobiotic substances in the risk to develop this disease has been claimed (3) and it cannot be excluded that any of these xenobiotics may be CYP2C9 substrates or inhibitors, thus modifying the risk factor studied. In addition, patients with ulcerative colitis also show an increased risk to develop colorectal cancer (4). Finally, the aetiology of irritable bowel syndrome is unknown and it cannot be ruled out the influence of xenobiotic substances in their pathogenesis.

Regarding the CYP2C9 allele frequency reported in the Spanish population (1), we agree that the reported frequency among Spaniards is higher than that reported for other Caucasians. Yasar et al., seem to assume that this is due to an atypical distribution of allele frequencies in our study group, rather than actual differences in CYP2C9 allele frequencies between diverse Caucasian populations. It seems simplistic to think that all Caucasian individuals have identical allele frequencies for genes involved in the metabolism of xenobiotic substances. Yasar et al., do not consider the conclusions drawn on the excellent reviews about this matter that have been published (5,6). A good example for this is the frequency for CYP2D6 gene duplication that is present in 1% of Swedish individuals (7), and 7% of Spaniards (8).

As a matter of fact, heterogeneity in the frequency of mutated CYP2C9 alleles in different Caucasian populations is likely to occur. We have reported previously in a different study allele frequencies that are almost identical to these reported in the control group analysed in the present paper (9). In addition, a preliminary report indicated a frequency over 15% for CYP2C9*3 in a rural US Caucasian population (10). Table IGo summarizes the mutated allele frequency observed in some CYP2C9 genotyping studies involving healthy individuals, and indicates a high variability in the allele frequency.


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Table I. Frequency for CYP2C9 gene variants in caucasian individuals from different geographic origin
 
After the publication of our study on colorectal cancer (1) we increased the sample size of our control group. Now we have analysed 197 healthy individuals and the allele frequencies remain almost identical to those published in the paper: 0.147 for the CYP2C9*2 allele and 0.15 for the CYP2C9*3 allele. Moreover, findings of ours reveal that Spanish lung cancer patients show mutated CYP2C9 allele frequencies of 0.154 for CYP2C9*2 and 0.135 for CYP2C9*3 (15). We must conclude that the high frequency for mutated genes observed among healthy subjects in the present study is not an isolated finding, and it is likely to be present in other healthy populations.

The cause for the variability in allele frequency may be due to the high degree of genetic admixture of individuals from South-European countries with North-African populations of Caucasian origin. Such admixture was especially relevant in Spain during the long period of Muslim domination, between the early 8th and the late 15th centuries. This causes an increased frequency of duplicated CYP2D6 alleles among South-European individuals, and can be also responsible for variation in the frequency of mutated CYP2C9 alleles. Aynacioglu et al., (12) showed that Turkish individuals have a CYP2C9*3 allele frequency that is slightly increased. This increase can be more important in North-African populations. In this regard, it should be kept in mind that several North-African populations (nearly 200 million people) are present in Morocco, Algeria, Tunisia, Libya, Egypt and Mauritania among other countries. In summary, minor differences on CYP2C9 allele frequency among Spaniards and other Caucasian individuals is anything but surprising.

The last sentence in the letter of Yasar et al., is highly speculative. It is obvious that differences on allele frequencies in case-control studies can be due to atypical distribution either in cases or in controls. Nevertheless, cases have different allele frequencies depending on the anatomical localization of the tumour. In fact, allele frequencies are almost identical among patients with rectum tumours and healthy subjects. Therefore, according to the reasoning of Yasar et al., the atypical distribution should be present in healthy subjects, among Spanish patients with rectal cancer (1) and among Spanish patients with lung cancer (15).

Notes

6 To whom correspondence should be addressed Email: jagundez{at}unex.es Back

References

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Received January 31, 2002; accepted January 31, 2002.