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COX-1 (PTGS1) and COX-2 (PTGS2) polymorphisms, NSAID interactions, and risk of colon and rectal cancers in two independent populations

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Abstract

Purpose

Nonsteroidal anti-inflammatory drugs (NSAIDs) target the prostaglandin H synthase enzymes, cyclooxygenase (COX)-1 and COX-2, and reduce colorectal cancer risk. Genetic variation in the genes encoding these enzymes may be associated with changes in colon and rectal cancer risk and in NSAID efficacy.

Methods

We genotyped candidate polymorphisms and tag SNPs in PTGS1 (COX-1) and PTGS2 (COX-2) in a population-based case–control study (Diet, Activity and Lifestyle Study, DALS) of colon cancer (n = 1,470 cases/1,837 controls) and rectal cancer (n = 583/775), and independently among cases and controls from the Colon Cancer Family Registry (CCFR; colon n = 959/1,535, rectal n = 505/839).

Results

In PTGS2, a functional polymorphism (−765G>C; rs20417) was associated with a twofold increased rectal cancer risk (p = 0.05) in the DALS. This association replicated with a significant nearly fivefold increased risk of rectal cancer in the CCFR study (ORCC vs. GG = 4.88; 95 % CI 1.54–15.45; ORGC vs. GG = 1.36; 95 %CI 0.95–1.94). Genotype–NSAID interactions were observed in the DALS for PTGS1 and rectal cancer risk and for PTGS2 and colon cancer risk, but were no longer significant after correcting for multiple comparisons and did not replicate in the CCFR. No significant associations between PTGS1 polymorphisms and colon or rectal cancer risk were observed.

Conclusions

These findings suggest that polymorphisms in PTGS2 may be associated with rectal cancer risk and impact the protective effects of NSAIDs.

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Acknowledgments

This work was supported by the National Cancer Institute, National Institutes of Health under RFA # CA-95-011, by Grants R01 CA114467, R01 CA112516, U24 CA074794, R25 CA094880, and R01 CA 48998, and through cooperative agreements with members of the Colon Cancer Family Registry and PIs. Funding was also provided for AJR by the National Cancer Institute Grant T32 CA09168 (Cancer Epidemiology and Biostatistics Training Grant). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. CCFR centers providing data for the analysis include the following: Australasian Colorectal Cancer Family Registry (U01 CA097735); Familial Colorectal Neoplasia Collaborative Group (U01 CA074799); Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800); Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); Seattle Colorectal Cancer Family Registry (U01 CA074794); University of Hawaii Colorectal Cancer Family Registry (U01 CA074806); and University of California, Irvine Informatics Center (U01 CA078296). The authors would like to thank Sandie Edwards for her contributions to the replication colon and rectal cancer studies. We also thank Darin Taverna, Jill Muehling, and Ling-Yu Kuan for genotyping assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA

    Karen W. Makar, Elizabeth M. Poole, Alexa J. Resler, Brenna Seufert, Sarah E. Kleinstein, Li Hsu, John Whitton, Christopher S. Carlson, Christine F. Rimorin, John D. Potter & Cornelia M. Ulrich

  2. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Elizabeth M. Poole

  3. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    Elizabeth M. Poole

  4. Department of Medicine, School of Medicine, University of Utah, Salt Lake City, UT, 84108, USA

    Karen Curtin & Martha L. Slattery

  5. Department of Epidemiology, University of Washington, Seattle, WA, 98109, USA

    Alexa J. Resler, John D. Potter & Cornelia M. Ulrich

  6. Translational Genomics, Phoenix, AZ, 85004, USA

    David Duggan

  7. University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Richard J. Kulmacz

  8. Department of Research, Kaiser Permanente Medical Research Program, Oakland, CA, 94611, USA

    Bette J. Caan

  9. Dartmouth Medical School, Lebanon, NH, USA

    John A. Baron

  10. University of North Carolina, Chapel Hill, NC, USA

    John A. Baron

  11. National Center for Tumor Diseases, German Cancer Research Center, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany

    Cornelia M. Ulrich

  12. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27708, USA

    Sarah E. Kleinstein

  13. Centre for Public Health Research, Massey University, Wellington, New Zealand

    John D. Potter

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  1. Karen W. Makar
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  2. Elizabeth M. Poole
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Correspondence to Cornelia M. Ulrich.

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Makar, K.W., Poole, E.M., Resler, A.J. et al. COX-1 (PTGS1) and COX-2 (PTGS2) polymorphisms, NSAID interactions, and risk of colon and rectal cancers in two independent populations. Cancer Causes Control 24, 2059–2075 (2013). https://doi.org/10.1007/s10552-013-0282-1

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