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© 2005 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Integrin 
3 Leu33Pro Homozygosity and Risk of Cancer
Affiliations of authors: Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark (SEB, BGN); The Copenhagen City Heart Study, Bispebjerg University Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark (AT-H, BGN); Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark (AT-H)
Correspondence to: Børge G. Nordestgaard, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark (e-mail: brno{at}herlevhosp.kbhamt.dk).
We thank Wang-Gohrke and Chang-Claude for their interesting comments to our article on integrin 
3 Leu33Pro homozygosity and increased risk for all cancer (1). In an exploratory posthoc analysis of 27 specific cancer types, we observed that women who carry the polymorphism (homozygotes) had a higher risk for ovarian cancer than noncarriers (hazard ratio [HR] = 4.7, 95% confidence interval [CI] = 1.6 to 14); however, this estimate was based on only 36 incident cases. Nevertheless, even after correction for the 27 multiple comparisons, increased risk of ovarian cancer in homozygotes remained statistically significant (1).
In a population-based, age-matched case–control study of 240 ovarian cancer case patients and 426 age-matched control subjects, Wang-Gohrke and Chang-Claude observed allele frequencies like ours (1) but no statistical significant difference in risk for ovarian cancer (odds ratio [OR] =1.23, 95% CI = 0.41 to 3.69) in integrin 3 Leu33Pro homozygotes versus noncarrier women, although their 95% confidence interval overlaps that in our study (1). Furthermore, in a yet unpublished case–control study of 463 ovarian cancer case patients and 3543 age-matched control subjects, we also observed a statistically significantly elevated odds ratio for ovarian cancer in Leu33Pro homozygotes versus non-carriers (Bojesen SE, Kjær SK, Hogdall EV, Thomsen BL, Hogdall CK, Blaakær J, et al.: unpublished data).
At least three main differences exist between the case–control study of Wang-Gohrke and Chang-Claude and that our studies. 1) Wang-Gohrke and Chang-Claude included 26 borderline tumors, whereas we included only invasive ovarian cancer. Excluding borderline tumors from their analyses will increase the odds ratio slightly, because it increases the frequency of homozygotes among case patients from 2.5% to 2.8%. 2) The statistical power (2) to exclude associations differed between the studies. The power of Wang-Gohrke and Chang-Claude to detect odds ratios of 2.0, 3.0, and 4.0 were 30%, 60%, and 80%, respectively, whereas the equivalent powers (Bojesen SE, Kjær SK, Hogdall EV, Thomsen BL, Hogdall CK, Blaakær J, et al.: unpublished data) were 76%, 100%, 100% in our case–control study and 29%, 58%, and 78% in our prospective study (1), respectively (Fig. 1). 3) The logistic regression analysis performed by Wang-Gohrke and Chang-Claude was adjusted for first-degree family history of ovarian cancer, whereas ours was not. Adjusting for family history in studies examining association between genetic factors and disease risk might eliminate the very association examined, because genetic mutations are often inherited. In conclusion, therefore, we cannot exclude the possibility that the results of the study of Wang-Gohrke and Chang-Claude are compatible with ours [Bojesen SE, Kjær SK, Hogdall EV, Thomsen BL, Hogdall CK, Blaakær J, et al.: unpublished data, (1)].
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Apart from examining the overall risk for ovarian cancer, Wang-Gohrke and Chang-Claude also examined the relevant issue of the association between Leu33Pro genotype and prognostic factors in patients with ovarian cancer. Interestingly, they observed a higher proportion of Leu33Pro carriers among case patients with adverse prognostic markers than in those without, which suggests that the integrin
3 Leu33Pro polymorphism is involved in the metastasis of and, therefore, an indicator of the malignant potential of ovarian cancer. Associations with prognostic factors and potential mechanisms should be explored further in future studies.
Functionally, the integrin 3 Leu33Pro polymorphism is an important polymorphism that was identified more than 40 years ago—this polymorphism is present in 79% of all case patients with neonatal alloimmune thrombocytopenia due to fetomaternal mismatch for human platelet allogens and is the most common cause of complications after platelet transfusion (3). The firm establishment of whether the 3 integrin Leu33Pro polymorphism also contributes to risk, metastasis, and/or the malignant potential of ovarian cancer awaits yet other studies.
REFERENCES
(1) Bojesen SE, Tybjærg-Hansen A, Nordestgaard BG. Integrin beta 3 Leu33Pro homozygosity and risk of cancer. J Natl Cancer Inst 2003;95:1150–7.
(2) NCSS 2001 and PASS 2000. Kaysville (UT): Number Cruncher Statistical Systems; 2001.
(3) Davoren A, Curtis BR, Aster RH, McFarland JG. Human platelet antigen-specific alloantibodies implicated in 1162 cases of neonatal alloimmune thrombocytopenia. Transfusion 2004;44:1220–5.[Medline]
Related Correspondence
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Connotea 
Del.icio.us What's this?
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: 778-779.
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  S E Bojesen, S K Kjaer, E V S Hogdall, B L Thomsen, C K Hogdall, J Blaakaer, A Tybjaerg-Hansen, and B G Nordestgaard Increased risk of ovarian cancer in integrin {beta}3 Leu33Pro homozygotes Endocr. Relat. Cancer, December 1, 2005; 12(4): 945 - 952. [Abstract] [Full Text] [PDF]
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