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JNCI Journal of the National Cancer Institute 2001 93(8):635-639; doi:10.1093/jnci/93.8.635
© 2001 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 93, No. 8, 635-639, April 18, 2001
© 2001 Oxford University Press

REPORT

Testing for Colon Neoplasia Susceptibility Variants at the Human COX2 Locus

Georgia L. Wiesner, Petra Platzer, Sarah Buxbaum, Susan Lewis, Mellissa MacMillen, Joseph Olechnowicz, Joseph Willis, Aravinda Chakravarti, Robert C. Elston, Sanford D. Markowitz

Affiliations of authors: G. L. Wiesner, Departments of Genetics and Medicine, Center for Human Genetics, and Ireland Comprehensive Cancer Center, Case Western Reserve University, and University Hospitals of Cleveland, OH; P. Platzer, S. D. Markowitz, Department of Medicine and Ireland Comprehensive Cancer Center, Case Western Reserve University, and University Hospitals of Cleveland, and Howard Hughes Medical Institute, Cleveland; S. Buxbaum, R. C. Elston, Department of Epidemiology and Biostatistics, and Ireland Comprehensive Cancer Center, Case Western Reserve University; S. Lewis, M. MacMillen, Department of Genetics, Center for Human Genetics, Case Western Reserve University, and University Hospitals of Cleveland; J. Olechnowicz, Ireland Comprehensive Cancer Center, Case Western Reserve University, and University Hospitals of Cleveland; J. Willis, Department of Pathology, Ireland Comprehensive Cancer Center, Case Western Reserve University, and University Hospitals of Cleveland; A. Chakravarti, Departments of Genetics and Medicine, Case Western Reserve University.

Correspondence to: Sanford D. Markowitz, M.D., Ph.D., 11001 Cedar Rd., Rm. 200, Cleveland, OH 44106 (e-mail: sxm10{at}po.cwru.edu).

Background: Siblings and other first-degree relatives of patients with "sporadic" (i.e., apparently nonfamilial) colorectal cancer or precursor adenomatous colon polyps have an increased risk of developing colon neoplasia. This observation suggests the presence of inherited genetic determinants for sporadic colon neoplasia. Mice homozygous for a null cyclooxygenase 2 (COX2) (also called PTGS2) allele have a dramatically reduced susceptibility to the development of intestinal adenomas. In humans, use of pharmacologic inhibitors of COX2 enzyme activity are associated with reduced risk of colon neoplasia. This study examined whether the human COX2 locus may be linked to colon neoplasia in humans. Methods: We used the affected sibling-pair method to test for linkage of the human COX2 locus to colon neoplasia. Results: We examined 74 concordantly affected sibling pairs from 46 sibships with colon neoplasia. One hundred five siblings from these sibships were diagnosed with either colorectal cancer or colon adenomatous polyps before age 65 years. No linkage between COX2 and colon neoplasia was found by use of a multipoint model-free linkage analysis (estimate of allele sharing was 0.44; standard error = ±0.04; 95% confidence interval = 0.36 to 0.52). Moreover, even allowing for heterogeneity, the potential that a COX2 colon neoplasia susceptibility variant was present within a substantial subset of these sibships was strongly excluded under either a recessive or a dominant inheritance model (95% confidence to exclude a model in which 2.7% or more of the sibling pairs harbor a dominant susceptibility allele). Conclusions: This study of concordantly affected sibling pairs thus demonstrates that variations in the COX2 gene are unlikely to be a source of individual susceptibility to colon neoplasia in humans.


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