Top

Published in:

01-10-2009 | Original paper

Effect of COX2 -765G>C and c.3618A>G polymorphisms on the risk and survival of sporadic colorectal cancer

Authors: Daniel Iglesias, Nargisse Nejda, Mariano Moreno Azcoita, Simó Schwartz Jr., Juan J. González-Aguilera, Antonia M. Fernández-Peralta

Published in: Cancer Causes & Control | Issue 8/2009

Abstract

Background

The COX2 gene (also known as PTGS2) encodes one of the essential cyclooxygenases for the prostanoid synthesis, and its expression is tightly regulated at both transcriptional and posttranscriptional levels. COX2 overexpression has been detected in up to 90% of colon carcinomas, and its downregulation inhibits polyp formation. Several polymorphisms located in both 5′- and 3′- flanking regions of COX2 have been described, but their functional significance and their use as prognostic indicators are still unclear.

Method

We analyzed in Spanish population the risk contribution and the prognostic significance for colorectal cancer (CRC) with five polymorphisms (rs20417, rs20426, rs5276, rs13306035 and rs4648298) located in the coding and regulatory regions of COX2.

Results

Only two variants appear in Spanish population: -765G>C (rs20417) located at the promoter and c.3618A>G (rs4648298) in the 3′UTR. None of the two polymorphisms associate with colon cancer risk (HR of 1.42; 95% CI = 0.46–4.47 and 0.62; 95% CI: 0.305–1.267, respectively). Moreover, the multifactor dimensionality reduction method does not detect high- or low-risk genotype combinations (training accuracy: 0.52; testing accuracy: 0.45; cross-validation consistency (CVC): 10/10; p = 0.37), indicating that there are no synergist interactions between these polymorphisms that alter the risk of cancer. However, the variant of the c.3618A>G polymorphism is associated with the presence of several clinicopathological features that have been shown to be good prognostic indicators. In addition, patients with the c.3618A>G polymorphism also show improved survival rates (log rank, p = 0.026).

Conclusion

The current results suggested that c.3618A>G polymorphism in COX2 is a good prognostic indicator for patients with CRC. Genotyping this polymorphism may be useful for predicting the clinical outcome of sporadic CRC.

Smith WL (1989) The eicosanoids and their biochemical mechanisms of action. Biochem J 259(2):315–324PubMed

Smith WL, Langenbach R (2001) Why there are two cyclooxygenase isozymes. J Clin Invest 107(12):1491–1495. doi:10.1172/JCI13271 PubMedCrossRef

Williams CS, Tsujii M, Reese J, Dey SK, DuBois RN (2000) Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 105(11):1589–1594. doi:10.1172/JCI9621 PubMedCrossRef

Jones R, Adel-Alvarez LA, Alvarez OR, Broaddus R, Das S (2003) Arachidonic acid and colorectal carcinogenesis. Mol Cell Biochem 253(1–2):141–149PubMed

Garavito RM, Malkowski MG, DeWitt DL (2002) The structures of prostaglandin endoperoxide H synthases-1 and -2. Prostaglandins Other Lipid Mediat 68–69:129–152. doi:10.1016/S0090-6980(02)00026-6 PubMed

Patrignani P, Tacconelli S, Sciulli MG, Capone ML (2005) New insights into COX-2 biology and inhibition. Brain Res Rev 48(2):352–359. doi:10.1016/j.brainresrev.2004.12.024 PubMedCrossRef

von Rahden BH, Stein HJ, Puhringer et al (2005) Coexpression of cyclooxygenases (COX-1, COX-2) and vascular endothelial growth factors (VEGF-A, VEGF-C) in esophageal adenocarcinoma. Cancer Res 65(12):5038–5044. doi:10.1158/0008-5472.CAN-04-1107 CrossRef

Appleby SB, Ristimaki A, Neilson K, Narko K, Hla T (1994) Structure of the human cyclo-oxygenase-2 gene. Biochem J 302(Pt 3):723–727PubMed

Yang X, Hou F, Taylor L, Polgar P (1997) Characterization of human cyclooxygenase 2 gene promoter localization of a TGF-beta response element. Biochim Biophys Acta 1350(3):287–292PubMed

10.

Papafili A, Hill MR, Brull DJ et al (2002) Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol 22(10):1631–1636. doi:10.1161/01.ATV.0000030340.80207.C5 PubMedCrossRef

11.

Cipollone F, Toniato E, Martinotti S et al (2004) Identification of new elements of plaque stability (INES) study group. A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. JAMA 291(18):2221–2228. doi:10.1001/jama.291.18.2221 PubMedCrossRef

12.

Wilusz CJ, Wormington M, Peltz SW (2001) The cap-to-tail guide to mRNA turnover. Nat Rev Mol Cell Biol 2(4):237–246. doi:10.1038/35067025 PubMedCrossRef

13.

Srivastava SK, Tetsuka T, Daphna-Iken D, Morrison AR (1994) IL-1 beta stabilizes COX II mRNA in renal mesangial cells: role of 3′-untranslated region. Am J Physiol 267(3 Pt 2):F504–F508PubMed

14.

Nishimori T, Inoue H, Hirata Y (2004) Involvement of the 3′-untranslated region of cyclooxygenase-2 gene in its post-transcriptional regulation through the glucocorticoid receptor. Life Sci 74(20):2505–2513. doi:10.1016/j.lfs.2003.10.017 PubMedCrossRef

15.

Cok SJ, Acton SJ, Morrison AR (2003) The proximal region of the 3′-untranslated region of cyclooxygenase-2 is recognized by a multimeric protein complex containing HuR, TIA-1, TIAR, and the heterogeneous nuclear ribonucleoprotein U. J Biol Chem 278(38):36157–36162. doi:10.1074/jbc.M302547200 PubMedCrossRef

16.

Subbaramaiah K, Marmo TP, Dixon DA, Dannenberg AJ (2003) Regulation of cyclooxgenase-2 mRNA stability by taxanes: evidence for involvement of p38, MAPKAPK-2, and HuR. J Biol Chem 278(39):37637–37647. doi:10.1074/jbc.M301481200 PubMedCrossRef

17.

Newton R, Seybold J, Liu SF, Barnes PJ (1997) Alternate COX-2 transcripts are differentially regulated: implications for post-transcriptional control. Biochem Biophys Res Commun 234(1):85–89. doi:10.1006/bbrc.1997.6586 PubMedCrossRef

18.

Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107(4):1183–1188PubMed

19.

Chapple KS, Cartwright EJ, Hawcroft G et al (2000) Localization of cyclooxygenase-2 in human sporadic colorectal adenomas. Am J Pathol 156(2):545–553PubMed

20.

Oshima M, Dinchuk JE, Kargman SL et al (1996) Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87(5):803–809. doi:10.1016/S0092-8674(00)81988-1 PubMedCrossRef

21.

Solomon SD, McMurray JJV, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352:1071–1080. doi:10.1056/NEJMoa050405 PubMedCrossRef

22.

Chan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356(21):2131–2142. doi:10.1056/NEJMoa067208 PubMedCrossRef

23.

Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Breazna A, Kim K, Tang J, Rosenstein RB, Umar A, Bagheri D, Collins NT, Burn J, Chung DC, Dewar T, Foley TR, Hoffman N, Macrae F, Pruitt RE, Saltzman JR, Salzberg B, Sylwestrowicz T, Hawk ET (2009) Adenoma prevention with celecoxib study investigators 5-year efficacy and safety analysis of the adenoma prevention with celecoxib trial. Cancer Prev Res (Phila Pa) 2(4):310–321. doi:10.1158/1940-6207.CAPR-08-0206

24.

Humar B, Giovanoli O, Wolf A et al (2000) Germline alterations in the cyclooxygenase-2 gene are not associated with the development of extracolonic manifestations in a large Swiss familial adenomatous polyposis kindred. Int J Cancer 87(6):812–817. doi:10.1002/1097-0215(20000915)87:6<812::AID-IJC9>3.0.CO;2-A PubMedCrossRef

25.

Fritsche E, Baek SJ, King LM, Zeldin DC, Eling TE, Bell DA (2001) Functional characterization of cyclooxygenase-2 polymorphisms. J Pharmacol Exp Ther 299(2):468–476PubMed

26.

Ritchie MD, Hahn LW, Roodi N et al (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69(1):138–147. doi:10.1086/321276 PubMedCrossRef

27.

Ritchie MD, Hahn LW, Moore JH (2003) Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol 24(2):150–157. doi:10.1002/gepi.10218 PubMedCrossRef

28.

Hahn LW, Ritchie MD, Moore JH (2003) Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics 19(3):376–382. doi:10.1093/bioinformatics/btf869 PubMedCrossRef

29.

Ulrich CM, Whitton J, Yu JH et al (2005) PTGS2 (COX-2) -765G>C promoter variant reduces risk of colorectal adenoma among nonusers of nonsteroidal anti-inflammatory drugs. Cancer Epidemiol Biomarkers Prev 14(3):616–619. doi:10.1158/1055-9965.EPI-04-0510 PubMedCrossRef

30.

Campa D, Zienolddiny S, Maggini V, Skaug V, Haugen A, Canzian F (2004) Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis 25(2):229–235. doi:10.1093/carcin/bgh008 PubMedCrossRef

31.

Cox DG, Pontes C, Guino E et al (2004) Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer. Br J Cancer 91(2):339–343PubMed

32.

Shahedi K, Lindstrom S, Zheng SL (2006) Genetic variation in the COX-2 gene and the association with prostate cancer risk. Int J Cancer 119(3):668–672. doi:10.1002/ijc.21864 PubMedCrossRef

33.

Gallicchio L, McSorley MA, Newschaffer CJ (2006) Nonsteroidal antiinflammatory drugs, cyclooxygenase polymorphisms, and the risk of developing breast carcinoma among women with benign breast disease. Cancer 106(7):1443–1452. doi:10.1002/cncr.21763 PubMedCrossRef

34.

Mehlen P, Fearon ER (2004) Role of the dependence receptor DCC in colorectal cancer pathogenesis. J Clin Oncol 22(16):3420–3428. doi:10.1200/JCO.2004.02.019 PubMedCrossRef

35.

Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767. doi:10.1016/0092-8674(90)90186-I PubMedCrossRef

36.

Saw RP, Koorey D, Painter D, Gallagher SolomonMJ (2002) p53, DCC and thymidylate synthase as predictors of survival after resection of hepatic metastases from colorectal cancer. Br J Surg 89(11):1409–1415PubMedCrossRef

37.

Karnes WE Jr, Shattuck-Brandt R, Burgart LJ et al (1998) Reduced COX-2 protein in colorectal cancer with defective mismatch repair. Cancer Res 58(23):5473–5477PubMed

38.

Fujita M, Fukui H, Kusaka T (2000) Relationship between cyclooxygenase-2 expression and K-ras gene mutation in colorectal adenomas. J Gastroenterol Hepatol 15(11):1277–1281. doi:10.1046/j.1440-1746.2000.02399.x PubMedCrossRef

39.

Sheng H, Shao J, Dixon DA et al (2000) Transforming growth factor-beta1 enhances Ha-ras-induced expression of cyclooxygenase-2 in intestinal epithelial cells via stabilization of mRNA. J Biol Chem 275(9):6628–6635. doi:10.1074/jbc.275.9.6628 PubMedCrossRef

40.

Sheng H, Shao J, Dubois RN (2001) K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B. Cancer Res 61(6):2670–2675PubMed

41.

Span M, Moerkerk PT, De Goeli AF, Arends JW (1996) A detailed analysis of K-ras point mutations in relation to tumor progression and survival in colorectal cancer patients. Int J Cancer 69(4):241–245. doi:10.1002/(SICI)1097-0215(19960621)69:3<241::AID-IJC15>3.0.CO;2-A PubMedCrossRef

42.

González-Aguilera JJ, Oliart S, Azcoita MM, Fernandez-Peralta AM (2004) Simultaneous mutations in K-ras and TP53 are indicative of poor prognosis in sporadic colorectal cancer. Am J Clin Oncol 27(1):39–45. doi:10.1097/01.coc.0000045920.49210.7A PubMedCrossRef

43.

Kressner U, Bjorheim J, Westring S et al (1998) Ki-ras mutations and prognosis in colorectal cancer. Eur J Cancer 34(4):518–521. doi:10.1016/S0959-8049(97)10111-3 PubMedCrossRef

44.

Newton R, Seybold J, Kuitert LM, Bergmann M, Barnes PJ (1998) Repression of cyclooxygenase-2 and prostaglandin E2 release by dexamethasone occurs by transcriptional and post-transcriptional mechanisms involving loss of polyadenylated mRNA. J Biol Chem 273(48):32312–32321. doi:10.1074/jbc.273.48.32312 PubMedCrossRef

45.

Dixon DA, Kaplan CD, McIntyre TM, Zimmerman GA, Prescott SM (2000) Post-transcriptional control of cyclooxygenase-2 gene expression. The role of the 3′-untranslated region. J Biol Chem 275(16):11750–11757. doi:10.1074/jbc.275.16.11750 PubMedCrossRef

46.

Cok SJ, Morrison AR (2001) The 3′-untranslated region of murine cyclooxygenase-2 contains multiple regulatory elements that alter message stability and translational efficiency. J Biol Chem 276(25):23179–23185. doi:10.1074/jbc.M008461200 PubMedCrossRef

Title: Effect of COX2 -765G>C and c.3618A>G polymorphisms on the risk and survival of sporadic colorectal cancer
Authors: Daniel Iglesias
Nargisse Nejda
Mariano Moreno Azcoita
Simó Schwartz Jr.
Juan J. González-Aguilera
Antonia M. Fernández-Peralta
Publication date: 01-10-2009
Publisher: Springer Netherlands
Published in: Cancer Causes & Control / Issue 8/2009
Print ISSN: 0957-5243
Electronic ISSN: 1573-7225
DOI: https://doi.org/10.1007/s10552-009-9368-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Method

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 8/2009

Comment on: Lacasse Y, Martin S, Gagne D, Lakhal L (2009) Dose–response meta-analysis of silica and lung cancer. Cancer Causes Control (e-published ahead of print) doi:10.1007/s10552-009-9296-0

Smoking attenuates the negative association between carotenoids consumption and colorectal cancer risk

Leukemia survival in children, adolescents, and young adults: influence of socioeconomic status and other demographic factors

Total dietary antioxidant index and survival in patients with glioblastoma multiforme

Neighborhood socioeconomic status influences the survival of elderly patients with myelodysplastic syndromes in the United States

Reply to: Dr. Peter Morfeld’s Letter to the Editor (Manuscript Number: CACO2009): “Comment on Lacasse Y, Martin S, Gagne D, Lakhal L (2009) Dose–response meta-analysis of silica and lung cancer. Cancer Causes and Control; [e-pub ahead of print] doi: 10.1007/s10552-009-9296-0”

Keynote webinar | Spotlight on antibody–drug conjugates in cancer