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Correspondence re: Zheng et al., Haplotype of Two Variants in p16 (CDKN2/MTS-1/INK4a) Exon 3 and Risk of Squamous Cell Carcinoma of the Head and Neck: a Case-Control Study. 11: 640–645, 2002

Department of Biosciences, Karolinska Institute, Novum 141 57 Huddinge, Sweden

Zheng et al. (1) have conducted a case-control study to determine the role of two polymorphisms in exon 3 of the CDKN2A gene in squamous cell carcinoma of head and neck. The two polymorphisms 500 CG² and 540 CT are located in the 3' untranslated region of the CDKN2A gene and are not part of the coding sequence. Recent studies provide sufficient evidence for the role of the 3' UTR of mRNA in regulation of gene expression (2) . The 3' UTR of the CDKN2A gene is common to two transcripts that encode p16^INK4a and p14^ARF cell cycle regulators. The effect of these two polymorphisms on the expression of these two transcripts, if any, remains unknown. The prevalence of one of these polymorphisms 500 CG has been shown to increase with increasing familial risk of melanoma (3) . Our studies on metastatic melanoma showed association of both these polymorphisms with decreased disease-free survival and association of the 500 CG polymorphism with reduced p53 expression (4) . In the same study and in subsequent studies (4, 5, 6) , we also showed the linkage disequilibrium between the 500 CG polymorphism and 74 CA polymorphism in intron 1 of the CDKN2B, which does not involve 540 CT as misquoted by Zheng et al. (1) . In our subsequent study on primary melanoma, we found overrepresentation of the 540 CT polymorphism compared with healthy controls (5) and also an association with low-grade vertical growth phase melanomas (7) . In our continued study on the role of these polymorphisms, we have extensively screened bladder cancer cases and found an association of these polymorphisms with tumour stage and survival.³

The method used for the study of both these polymorphisms simultaneously and, consequently haplotype analysis, was described by us in our initial study of sporadic primary melanoma (8) , and it has been used in all our above mentioned studies (4, 5, 6, 7, 8) . Our primer pair and SSCP conditions for the amplification of exon 3 and detection of polymorphisms were copied by Zheng et al. (1) . We are happy to know that primer pair and SSCP conditions described by us (8) have functioned well in a study carried out in a different laboratory. However, Zheng et al. (1) have wrongly attributed this primer pair to a study (9) in which exon 3 of CDKN2A was never analyzed and claim to have developed a method, which we have described in our above mentioned studies (4, 5, 6, 7, 8) . In support of their claim, they refrain from referring to our published method. Moreover, the sequence of the forward primer, located in the intron, is from the reported sequence with GenBank accession no. U12820 and not L27211 (mRNA sequence of p16^INK4a transcript of the CDKN2A gene) as claimed by Zheng et al. (1) .

Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ E-mail: rajiv.kumar{at}cnt.ki.se

² The numbers used for describing the polymorphisms refer to the nucleotide position with respect to ATG start codon of the CDKN2A (p16) cDNA sequence. However, the numbers used by Zheng et al. (1) are based on the nucleotide position in the GenBank sequence L27211.

³ S. Sakano, P. Berggren, R. Kumar, G. Steineck, J. Adolfsson, E. Önelov, K. Hemminki, and P. Larsson: Int. J. Cancer, in press.

Received 7/25/02; revised 7/25/02; accepted 8/19/02.

References

1. Zheng Y., Shen H., Sturgis E. M., Wang L. E., Shete S., Spitz M. R., Wei Q. Haplotypes of two variants in p16 (CDKN2/MTS-1/INK4a) exon 3 and risk of squamous cell carcinoma of the head and neck: a case-control study. Cancer Epidemiol. Biomark. Prev., 11: 640-645, 2002.[Abstract/Free Full Text]
2. Conne B., Stutz A., Vassalli J. D. The 3' untranslated region of messenger RNA: a molecular ‘hotspot‘ for pathology?. Nat. Med., 6: 637-641, 2000.[Medline]
3. Aitken J., Welch J., Duffy D., Milligan A., Green A., Martin N., Hayward N. CDKN2A variants in a population-based sample of Queensland families with melanoma. J. Natl. Cancer Inst. (Bethesda), 91: 446-452, 1999.[Abstract/Free Full Text]
4. Sauroja I., Smeds J., Vlaykova T., Kumar R., Talve L., Hahka-Kemppinen M., Punnonen K., Jansen C. T., Hemminki K., Pyrhonen S. Analysis of G₁S checkpoint regulators in metastatic melanoma. Genes Chromosomes Cancer, 28: 404-414, 2000.[Medline]
5. Kumar R., Smeds J., Berggren P., Straume O., Rozell B. L., Akslen L. A., Hemminki K. A single nucleotide polymorphism in the 3' untranslated region of the CDKN2A gene is common in sporadic primary melanomas but mutations in the CDKN2B, CDKN2C, CDK4, and p53 genes are rare. Int. J. Cancer, 95: 388-393, 2001.[Medline]
6. Smeds J., Berggren P., Ma X., Xu Z., Hemminki K., Kumar R. Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: the CDKN2A (p16(INK4a) and p14(ARF) and p53 genes are major targets for inactivation. Carcinogenesis (Lond.), 23: 645-655, 2002.[Abstract/Free Full Text]
7. Straume O., Smeds J., Kumar R., Hemmiki K., Akslen L. A. Significant impact of promoter hypermethylation and the CT polymorphism of CDKN2A in cutaneous melanoma of the vertical growth phase. Am. J. Pathol., 161: 229-237, 2002.[Abstract/Free Full Text]
8. Kumar R., Lundh Rozell B., Louhelainen J., Hemminki K. Mutations in the CDKN2A (p16INK4a) gene in microdissected sporadic primary melanomas. Int. J. Cancer, 75: 193-198, 1998.[Medline]
9. Miracca E. C., Kowalski L. P., Nagai M. A. High prevalence of p16 genetic alterations in head and neck tumours. Br. J. Cancer, 81: 677-683, 1999.[Medline]

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