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© 2005 Oxford University Press
CORRESPONDENCE |
Re: Integrin 
3 Leu33Pro Homozygosity and Risk of Cancer
Affiliations of authors: Molecular Biology Laboratory, Department of Obstetrics & Gynecology, University of Ulm, Prittwitzstrasse 43, D-89075 Ulm, Germany (SWG); Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Postfach 101949, 69009 Heidelberg, Germany (JCC)
Correspondence to: For correspondence regarding molecular biology: Shan Wang-Gohrke, MD, Department of Obstetrics and Gynecology, University of Ulm, Prittwitzstrasse 43, D-89075 Ulm, Germany (e-mail: shan.wang{at}medizin.uni-ulm.de); for correspondence regarding epidemiology: Jenny Chang-Claude, PhD, Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Postfach 101949, 69009 Heidelberg, Germany (e-mail: J.Chang-Claude{at}dkfz.de).
Integrins are transmembrane 
heterodimers that function as key surface adhesion and cell signaling receptors influencing cell proliferation and migration. Overexpression of integrin 3 is associated with progression to invasive tumors, whereas inhibition of 3 integrin expression and/or function is associated with a reduction in tumor growth and metastasis. Specific 3 integrin inhibitors are being developed as cancer drugs, some of which are already in clinical trials.
A functional polymorphism at codon 33 (leucine to proline [Leu33Pro]) of the integrin 3 was reported in the Journal to be associated with the risk of ovarian cancer in a Danish prospective population-based study, with individuals homozygous for the 33-proline allele having a fourfold statistically significantly increased risk (1). We used a population-based age-matched case–control study among German white women to determine whether the integrin 3 Leu33Pro polymorphism is associated with ovarian cancer risk. As described previously (2), patients were diagnosed with incident ovarian cancer and two control subjects, matched by exact age and study region, per case subject were selected from random lists of residents supplied by the population registries. The study was approved by the ethics committee of the University of Heidelberg. The clinical characteristics of the patients were classified according to the International Federation of Gynecology and Obstetrics (FIGO) staging (Table 1). Integrin Leu33Pro polymorphism was genotyped using the previously described polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay (1). The analysis was restricted to 240 case subjects (mean age = 56.1 years) and 426 control subjects (mean age = 55.5 years) who provided a blood sample and have at least one parent of German nationality. Because of the size of our study, we had more than 95% statistical power to detect an odds ratio of 4.0 or above at a 5% significance level (two-sided) based on the 2.7% subjects homozygous for the 33-proline allele in the Danish study (1).
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The frequency of the proline allele of 0.14 in the control subjects of our study population was similar to previous reports (1,3). We observed neither deviation from the expected Hardy–Weinberg distribution nor a statistically significant difference in the genotype distribution between the case and control groups. The adjusted odds ratio of ovarian cancer for carriers of the 33-proline allele was 0.89 (95% confidence interval [CI] = 0.59 to 1.34) (Table 1). We did not observe a statistically significant increase in risk among homozygote carriers of the 33-proline allele (OR = 1.23, 95% CI = 0.41 to 3.69) as reported by Bojesen et al. (RR = 4.7, 95% CI = 1.6 to 14) (1).
We found a statistically significant higher proportion of 33-proline allele carriers among those with higher FIGO-staged disease (Ptrend = .02) (Table 1), which was not reported by Bojesen et al. (1). Moreover, when patients were stratified by borderline tumor status (i.e., ovarian tumors of low malignant potential with a very favorable prognosis), we found a higher proportion of 33-proline allele carriers among patients without borderline tumors than among patients with borderline tumors, although the difference in the proportion was not statistically significant (Fisher's exact test, P = .11; Table 1). These data provide a possible indication of the involvement of integrin Leu33Pro polymorphism in the metastasis and malignant potential of ovarian cancer. Our findings are compatible with laboratory observations that the integrin Leu33Pro polymorphism is associated with increased reactivity and aggregability of platelets in vitro (4,5) and with increased cell cycle progression or proliferation of tumor cells through extracellular signal–related kinase (6,7), which has an impact on metastasis and malignant potential of ovarian cancer. We conclude that the integrin Leu33Pro polymorphism does not modify ovarian cancer risk in German women but that it may influence the metastatic spread and the malignant potential of ovarian cancer.
REFERENCES
(1) Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. Integrin beta3 Leu33Pro homozygosity and risk of cancer. J Natl Cancer Inst 2003;95:1150–7.
(2) Royar J, Becher H, Chang-Claude J. Low-dose oral contraceptives: protective effect on ovarian cancer risk. Int J Cancer 2001;95:370–4.[CrossRef][Web of Science][Medline]
(3) Jin Q, Hemminki K, Grzybowska E, Klaes R, Soderberg M, Forsti A. Re: Integrin beta3 Leu33Pro homozygosity and risk of cancer. J Natl Cancer Inst 2004;96:234–5.
(4) Michelson AD, Furman MI, Goldschmidt-Clermont P, Mascelli MA, Hendrix C, Coleman L, et al. Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists. Circulation 2000;101:1013–8.
(5) Vijayan KV, Liu Y, Dong JF, Bray PF. Enhanced activation of mitogen-activated protein kinase and myosin light chain kinase by the Pro33 polymorphism of integrin beta 3. J Biol Chem 2003;278:3860–7.
(6) Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002;298:1911–2.
(7) Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3:11–22.[CrossRef][Web of Science][Medline]
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3 Leu33Pro Homozygosity and Risk of Cancer
J Natl Cancer Inst 2004 96: 234-235.
3 Leu33Pro Homozygosity and Risk of Cancer
J Natl Cancer Inst 2005 97: 779-780.
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