CORRESPONDENCE

RESPONSE: Testing for Colon Neoplasia Susceptibility Variants at the Human COX2 Locus

Georgia L. Wiesner, Petra Platzer, Sarah G. Buxbaum, Susan Lewis, Melissa Macmillen, Joseph Willis, Aravinda Chakravarti, Robert C. Elston, Sanfor 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, 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. G. Buxbaum, R. C. Elston, Department of Epidemiology and Biostatistics and Ireland Cancer Center, Case Western Reserve University; S. Lewis, M. MacMillen, Department of Genetics and the Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland; J. Willis, Department of Pathology and Ireland Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland; A. Chakravarti, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University, Baltimore, MD.

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

We thank Drs. Ulrich and Potter for their thoughtful comments and appreciate the opportunity to clarify any potential misconceptions regarding our recent study (1).

Drs. Ulrich and Potter express the concern that the population we studied includes individuals at low risk (small adenomas) but also is a group at high risk and hence not representative of the general population. Our study population most accurately is one at moderately elevated risk. Of 105 affected persons in the study, 85 had either cancer, multiple adenomas, or an adenoma greater than 0.5 cm in size, versus the general population, in which 21%–35% of individuals aged 50–59 years bear colon adenomas (2). Our study was motivated by several prior studies suggesting that a common genetic component contributes to the risk of both "sporadic" colon cancers and their recognized precursors, colon adenomas (3,4). Our population was selected to enrich for this genetic component of sporadic colon neoplasia risk. While complete certitude is never possible, it is certainly reasonable to conclude that, in the absence of COX2 variation contributing to disease in a population enriched for genetic risk, it is unlikely that this locus would contribute to disease susceptibility within a lower risk population.

Drs. Ulrich and Potter have also raised the concern that our markers, which flank the COX2 locus at 0.6–1.4 cM between the markers, are too far distant to assay COX2 genetic variation. This concern would most properly apply if our study were an association study employing marker alleles to act as surrogates to track specific COX2 allelic variants in genetic disequilibrium with the markers. However, our study was a linkage, not an association, study. For linkage, markers are used only to determine if two siblings in the same family have inherited the same of the four distinguishable parental COX2 alleles (that in different families could well harbor different susceptibility variants). At less than 2% recombination distance, our markers are highly robust for tracking COX2 gene segregation within a family and for assessing linkage to the presence of colon neoplasia.

Drs. Ulrich and Potter also suggest that a sibling-pair study will not detect a COX2 genotype acting only in concert with a specific environmental exposure. However, a strength of our sibling-pair study design is that it analyzed the genetic component of disease risk among individuals all actually affected by colon neoplasia. Thus, the individuals among whom we have excluded an effect of COX2 variation represent and share those environmental exposures that are common to persons who have developed colonic neoplasms.

We agree with Drs. Ulrich and Potter's conclusion that any study should be interpreted with caution and that more can always be learned by repeating a study in a different population. However, we also suggest that the major genetic component of risk for sporadic colon neoplasia likely lies elsewhere in the genome than COX2. We are currently initiating a colon neoplasia sibling-pair based whole-genome scan, with the hope that this approach will serve to identify those regions of the genome where further effort can most profitably be directed.

REFERENCES

1 Wiesner GL, Platzer P, Buxbaum S, Lewis S, MacMillen M, Olechnowicz J, et al. Testing for colon neoplasia susceptibility variants at the human COX2 locus. J Natl Cancer Inst 2001;93:635–9.[Abstract/Free Full Text]

2 Markowitz AJ, Winawer SJ. Management of colorectal polyps. CA Cancer J Clin 1997;47:93–112.[Free Full Text]

3 Winawer SJ, Zauber AG, Gerdes H, O'Brien MJ, Gottlieb LS, Sternberg SS, et al. Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med 1996;334:82–7.[Abstract/Free Full Text]

4 Cannon-Albright LA, Skolnick MH, Bishop DT, Lee RG, Burt RW. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med. 1988;319:533–7.[Abstract]



             
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