CORRESPONDENCE

RESPONSE: Re: Integrin {beta}3 Leu33Pro Homozygosity and Risk of Cancer

Stig E. Bojesen, Anne Tybjærg-Hansen, Børge G. Nordestgaard

Affiliations of authors: Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark (SEB, BGN); The Copenhagen City Heart Study, Bispebjerg University Hospital, Copenhagen, Denmark (ATH, BGN); Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen (ATH).

Correspondence to: Børge G. Nordestgaard, MD, DMSc, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark (e-mail: brno{at}herlevhosp.kbhamt.dk)

We thank Jin et al. for their comments and for providing more data on the importance of integrin {beta}3 Leu33Pro homozygosity for risk of cancer. In 9242 individuals, aged 20–95 years, sampled from the Danish general population and followed prospectively for 24 years, we observed a relative risk of all cancers in 33Pro/Pro homozygotes versus noncarriers of 1.4 (95% confidence interval [CI] = 1.1 to 1.9) (1). When the 1660 primary cancers were separated into 27 different subtypes, relative risks in homozygotes versus noncarriers were 4.7 (95% CI = 1.6 to 14), 1.9 (95% CI = 1.0 to 3.7), and 3.5 (95% CI = 1.1 to 12) for ovarian cancer, breast cancer, and melanoma, respectively. Because P is equal to .06 for breast cancer, this finding could be due to chance alone, particularly because we did not correct for multiple comparisons.

In accordance with this possibility, Jin et al. did not find a statistically significant association between 33Pro/Pro homozygosity and breast cancer risk. However, like our study, their study has limitations. First, they included heterogeneous groups of breast cancer case and control subjects, with case subjects who were ascertained by four different methods from three different countries and who were not matched with control subjects for age and sex (2,3). Second, their study had limited statistical power to exclude an odds ratio of 1.9 for breast cancer in homozygotes versus noncarriers, equivalent to the hazard ratio of 1.9 observed in our study (1).

We used NCSS 2001 and PASS 2000 power calculation software (4) and a logistic regression power analysis to show that the power in the case–control study by Jin et al. to detect an odds ratio of 1.9 was 35% (Fig. 1). This suggests that an odds ratio of 1.9 could have been overlooked in their study. Jin et al. had "more than 90% power to detect a 1.6-fold increased risk of breast cancer" in heterozygotes and homozygotes combined versus noncarriers, and for the 33Pro allele versus the 33Leu allele; however, our study showed that risk in heterozygotes and noncarriers did not differ (1).



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Fig. 1. Statistical power as a function of hazard ratio in our prospective study (1) of all cancer (2.7% Pro/Pro homozygotes, 1296 incident cases among 9036 participants from the general population) and of breast cancer (2.8% Pro/Pro homozygotes in women, 195 incident cases among 5080 women), and as a function of odds ratio in the case–control study by Jin et al. (1.7% Pro/Pro homozygotes among 779 control subjects, 886 case subjects). Assumptions are 1) P = .05 on a two-sided test and 2) homozygotes are compared with noncarriers and heterozygotes combined. When homozygotes were compared with noncarriers only (excluding heterozygotes from the calculations), the power was slightly less than shown. Filled triangles = prospective study, all cancer (1); filled circles = prospective study, breast cancer (1); open circles = case–control study by Jin et al.

 
For comparison, with respect to total cancer and breast cancer risk using a log-rank survival power analysis (4), the power of our prospective study to detect a hazard ratio for breast cancer of 1.9 was 52% (Fig. 1). The case–control study by Ayala et al. (5) had only 7% power to detect an odds ratio of 1.9 for breast cancer in homozygotes versus noncarriers.

In conclusion, although our study suggests that 33Pro/Pro homozygosity of the {beta}3 subunit of integrins is associated with an increased risk of all cancer (1), the finding that this risk is, in part, due to breast cancer is based on limited statistical power. Because the study by Jin et al. does not have more statistical power than our own study, we do not agree that their study "provides strong evidence that the {beta}3 integrin Leu33Pro polymorphism does not appreciably modify breast cancer risk." We rather prefer to conclude that this issue is unresolved, and that other large, preferably prospective population-based studies are needed.

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.[Abstract/Free Full Text]

2 Försti A, Jin Q, Grzybowska E, Soderberg M, Zientek H, Sieminska M, et al. Sex hormone-binding globulin polymorphisms in familial and sporadic breast cancer. Carcinogenesis 2002;23:1315–20.[Abstract/Free Full Text]

3 Meindl A. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer 2002;97:472–80.[CrossRef][ISI][Medline]

4 NCSS 2001 and PASS 2000. Kaysville (UT): Number Cruncher Statistical Systems, 2001.

5 Ayala F, Corral J, Gonzalez-Conejero R, Sanchez I, Moraleda JM, Vicente V. Genetic polymorphisms of platelet adhesive molecules: association with breast cancer risk and clinical presentation. Breast Cancer Res Treat 2003;80:145–54.[CrossRef][ISI][Medline]



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