© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 20, 1572-1573,
October 17, 2001
© 2001 Oxford University Press
CORRESPONDENCE |
Testing for Colon Neoplasia Susceptibility Variants at the Human COX2 Locus
Affiliations of authors: Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, and Department of Epidemiology, University of Washington, Seattle.
Correspondence to: Cornelia M. Ulrich, Ph.D, Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, MP-900, Seattle, WA 98109–1024 (e-mail: nulrich{at}fhcrc.org).
Wiesner et al. (1) recently presented data from a sibling-pair study. Clearly, the cyclooxygenase (COX) pathway is of great interest to colorectal carcinogenesis, and functional polymorphisms in the COX2 gene may be important modifiers of disease risk. Wiesner et al. used an innovative approach to investigate genetic variability near the COX2 locus. However, the conclusions drawn by the authors may be overly generalized.
Wiesner et al. (1) concluded, "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" and "the COX2 locus is highly unlikely to harbor colon neoplasia susceptibility variants in any substantial fraction of the general human population."
A number of limitations reduce the capacity to draw these conclusions. First, although the authors excluded patients with hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis, the sibling-pair study population was at high risk, consisting of 25 colorectal cancer and 80 adenoma patients from 46 sibships, all diagnosed with colorectal cancer or adenomatous polyps by age 65 years. Consequently, the mean onset of cancers was 52.8 years—substantially lower than the average age of onset of colorectal cancer in the general population (72 years) (Surveillance, Epidemiology, and End Results [SEER]1Cancer Incidence Public-Use Database, 1973–1995). The generalizability of the study findings to the general population and to the risk of nonfamilial cancers is questionable.
Second, both adenomas and cancers were included in the sibships, and no information on characteristics of the cancer/adenoma was given. It may not be appropriate to equate small adenomas and frank cancers when designating individuals as "affected."
Third, the authors investigated two markers, D1S191 and D1S2848, at 0.6 and 1.4 cM from the COX2 locus. Because these markers are at substantial distances from the COX2 gene, this still leaves the possibility open that genetic variation at the COX2 locus itself is directly associated with disease risk.
Finally, our group and other investigators (2–5) have found that polymorphic genotypes are usually associated with substantially altered risk of colorectal neoplasia only in combination with relevant exposures. There are two ways in which specific polymorphisms might alter risk of cancer. If the underlying gene/protein function is central to the process of carcinogenesis, the consequences of a polymorphism may be detected as a main effect in a case–control (association) study and probably also with the use of a sibling-pair design. However, if the polymorphism alters the function of the gene/protein that interacts with or metabolizes a substrate (endogenous or exogenous) that itself increases or decreases risk, the consequences of a polymorphism will be detectable in a case–control study only in the presence versus the absence of the exposure (interaction). It will probably not be detected in a sibling-pair study and will certainly not be detected in the absence of data on relevant exposures.
Thus, although this study provides interesting information and uses innovative methods, more caution in the interpretation of the results may be appropriate. Further research on the potential role of genetic variability at the COX2 locus is still warranted.
NOTES
1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research. 
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.
2
Ulrich CM, Kampman E, Bigler J, Schwartz SM, Chen C, Bostick R, et al. Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene–environment interaction? Cancer Epidemiol Biomarkers Prev 1999;8:659–68.
3
Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 1997;57:1098–102.
4
Potter JD, Bigler J, Fosdick L, Bostick RM, Kampman E, Chen C, et al. Colorectal adenomatous and hyperplastic polyps: smoking and N-acetyltransferase 2 polymorphisms. Cancer Epidemiol Biomarkers Prev 1999;8:69–75.
5
Ulrich CM, Bigler J, Whitton JA, Bostick R, Fosdick L, Potter JD. Epoxide hydrolase Tyr113his polymorphism is associated with elevated risk of colorectal polyps in the presence of smoking and high meat intake. Cancer Epidemiol Biomarkers Prev 2001;10:875–82.
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