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© 2005 Oxford University Press
CORRESPONDENCE |
Re: Association of a Common Variant of the CASP8 Gene With Reduced Risk of Breast Cancer
Affiliations of authors: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany (BF, JLB, KH, BB); Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden (KH); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (RK); Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessia, University of Heidelberg, Faculty of Clinical Medicine, Mannheim, Germany (PB); Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Germany (BW, RKS)
Correspondence to: Bernd Frank, PhD, German Cancer Research Center (DKFZ), Division of Molecular Genetic Epidemiology, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany (e-mail: b.frank{at}dkfz.de).
Recently, MacPherson et al. (1) reported an association between the common caspase-8 (CASP8) gene variant D302H and reduced breast cancer risk. They studied two independent U.K. cohorts from Sheffield and East Anglia and observed statistically significant lower frequencies of the CASP8 DH and HH genotypes in both case patient populations compared with the respective control subjects, considering D302H as causative variant in a dose-dependent manner.
We investigated the influence of the D302H variant on familial breast cancer risk using a German study cohort. Detailed information regarding the design and methods of this case–control study has been described elsewhere (2). In brief, we recruited a study population of 355 breast cancer case patients and 1098 control individuals. The case patients were unrelated German women (mean age = 44.7 years, range = 21–80 years) without BRCA1/2 mutations. The control subjects were healthy, unrelated female blood donors (mean age = 41.0 years, range = 18–68 years) with the same ethnic background as the breast cancer case patients. The study was approved by the Ethics Committee of the University of Heidelberg, Germany.
Genotype-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression and adjusted for age. A one-sided Cochran–Armitage trend test was used to assess the change of breast cancer risk with the number of carried alleles. The computations were performed using SAS, version 8.2.
We observed lower frequencies of the DH and HH CASP8 D302H genotypes in case patients compared with control subjects (21.4% versus 23.7% and 1.1% versus 2.1%, respectively; Table 1). Genotype frequencies in case patients and in control subjects were consistent with Hardy–Weinberg equilibrium. The adjusted odds ratios were 0.87 (95% CI = 0.65 to 1.17; P = .35) for the DH heterozygotes versus the DD homozygotes and 0.49 (95% CI = 0.17 to 1.44; P = .20) for the HH homozygotes versus the DD homozygotes. The Cochran–Armitage test for trend also suggested a dose-dependent association between allele type and breast cancer risk (Ptrend = .077). These data are widely comparable to those of the Sheffield and East Anglia studies (1), although our results did not reach statistical significance.
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Multiple reasons exist that might account for the slight differences found between the study by MacPherson et al. and our study. The sample size of our study was smaller than that of the MacPherson et al. study. We had 90% power to detect an odds ratio of 0.54 or less (3). In contrast to standard case–control association studies, this study comprised case patients selected for family history of breast cancer (4), thus likely improving the above-mentioned power (5). In addition, unrecognized environmental factors may exist that modify the genetic association of caspase-8 and breast cancer risk, and they may vary between populations.
In conclusion, our case–control study supports results recently published by the Journal (1). Our data point to a dose-dependent association between carrying the CASP8 D302H allele and a reduced risk of breast cancer, although it lacks statistical significance.
NOTES
We thank Kerstin Wagner for critical comments on the manuscript and are grateful to C. R. Bartram (Heidelberg) and R. K. Schmutzler (Cologne, Germany) for providing the German breast cancer samples as part of a project funded by the Deutsche Krebshilfe.
REFERENCES
(1) MacPherson G, Healey CS, Teare MD, Balasubramanian SP, Reed MW, Pharoah PD, et al. Association of a common variant of the CASP8 gene with reduced risk of breast cancer. J Natl Cancer Inst 2004;96:1866–9.
(2) Frank B, Hemminki K, Wirtenberger M, Bermejo JL, Bugert P, Klaes R, et al. The rare ERBB2 variant Ile654Val is associated with an increased familial breast cancer risk. Carcinogenesis 2005;26:643–7.
(3) Dupont WD, Plummer WD Jr. Power and sample size calculations for studies involving linear regression. Control Clin Trials 1998;19:589–601.
(4) Meindl A; German Consortium for Hereditary Breast and Ovarian Cancer. 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][Web of Science][Medline]
(5) Antoniou AC, Easton DF. Polygenic inheritance of breast cancer: implications for design of association studies. Genet Epidemiol 2003;25:190–202.[CrossRef][Web of Science][Medline]
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J Natl Cancer Inst 2005 97: 1012-1013.
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