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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)635-639
Number of pages5
JournalJournal of the National Cancer Institute
Volume93
Issue number8
StatePublished - Apr 18 2001
Externally publishedYes

Fingerprint

Cyclooxygenase 2
Colon
Siblings
Neoplasms
Adenomatous Polyps
Alleles
Colorectal Neoplasms
Cyclooxygenase 2 Inhibitors
Adenoma
Colonic Neoplasms
Confidence Intervals
Enzymes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wiesner, G. L., Platzer, P., Buxbaum, S., Lewis, S., MacMillen, M., Olechnowicz, J., ... Markowitz, S. D. (2001). Testing for colon neoplasia susceptibility variants at the human COX2 locus. Journal of the National Cancer Institute, 93(8), 635-639.

Testing for colon neoplasia susceptibility variants at the human COX2 locus. / Wiesner, Georgia L.; Platzer, Petra; Buxbaum, Sarah; Lewis, Susan; MacMillen, Mellissa; Olechnowicz, Joseph; Willis, Joseph; Chakravarti, Aravinda; Elston, Robert C.; Markowitz, Sanford D.

In: Journal of the National Cancer Institute, Vol. 93, No. 8, 18.04.2001, p. 635-639.

Research output: Contribution to journalArticle

Wiesner, GL, Platzer, P, Buxbaum, S, Lewis, S, MacMillen, M, Olechnowicz, J, Willis, J, Chakravarti, A, Elston, RC & Markowitz, SD 2001, 'Testing for colon neoplasia susceptibility variants at the human COX2 locus', Journal of the National Cancer Institute, vol. 93, no. 8, pp. 635-639.
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. Journal of the National Cancer Institute. 2001 Apr 18;93(8):635-639.
Wiesner, Georgia L. ; Platzer, Petra ; Buxbaum, Sarah ; Lewis, Susan ; MacMillen, Mellissa ; Olechnowicz, Joseph ; Willis, Joseph ; Chakravarti, Aravinda ; Elston, Robert C. ; Markowitz, Sanford D. / Testing for colon neoplasia susceptibility variants at the human COX2 locus. In: Journal of the National Cancer Institute. 2001 ; Vol. 93, No. 8. pp. 635-639.
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abstract = "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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T1 - Testing for colon neoplasia susceptibility variants at the human COX2 locus

AU - Wiesner, Georgia L.

AU - Platzer, Petra

AU - Buxbaum, Sarah

AU - Lewis, Susan

AU - MacMillen, Mellissa

AU - Olechnowicz, Joseph

AU - Willis, Joseph

AU - Chakravarti, Aravinda

AU - Elston, Robert C.

AU - Markowitz, Sanford D.

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N2 - 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.

AB - 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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