© 2005 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Association of a Common Variant of the CASP8 Gene With Reduced Risk of Breast Cancer
Affiliation of authors: University of Sheffield, Institute for Cancer Studies, Sheffield, UK
Correspondence to: Angela Cox, PhD, University of Sheffield, Institute for Cancer Studies, G Floor, Medical School Beech Hill Rd., Sheffield, S10 2RX, UK (e-mail: a.cox{at}shef.ac.uk).
We read with interest the letter from Frank et al., which describes an analysis of the caspase-8 (CASP8) D302H gene variant in 355 familial breast cancer case patients and 1098 control subjects from Germany. Their results, although not statistically significant, suggest a dose-dependent association of the H allele with a reduced risk of breast cancer. This is consistent with the results we obtained from Sheffield and East Anglian study samples in the United Kingdom (1). To evaluate the overall evidence for the CASP8 D302H association, we used logistic regression adjusting for study sample. The resulting odds ratios were 0.84 (95% confidence interval [CI] = 0.75 to 0.94, P = .003), for the DH heterozygote and 0.58 (95% CI = 0.39 to 0.84, P = .004) for the HH homozygote genotypes. The odds ratios from the German study are consistent with the original estimates, and there was no evidence of heterogeneity between study samples (Mantel–Haenszel test for homogeneity of odds ratios, P = .75 and P = .98, respectively). The point estimate of the homozygote odds ratio is slightly (but not statistically significantly) lower for the German study than for the Sheffield and East Anglian studies (0.49 versus 0.58). This difference may reflect the fact that associations between genetic traits and disease risk are more extreme in those with a family history of the disease (2)—the German study population comprised women with a family history of breast cancer, in contrast to the women in the U.K. study population, who were not selected for family history.
The combined data are consistent with a multiplicative model for the effect of the H allele, with the overall evidence being very strongly statistically significant (Ptrend = 7.4 x 10–5). In our original report (1), we discussed the false-positive report probability (FPRP) of our observations as described by Wacholder et al. (3). Given that D302H is a nonsynonymous single nucleotide polymorphism, we assumed a prior probability of .001 for its association with breast cancer (3). Using this assumption, and after adding the data from Frank et al., the FPRP is reduced from .27 to .10. Thus, the available data so far yield strong evidence that the D302H single nucleotide polymorphism is associated with breast cancer susceptibility. However, to thoroughly evaluate the effect of this variant, it should be investigated in other large case–control data sets around the world. Functional studies are also required to determine whether the CASP8 D302H variant has a direct role in the apoptotic response and tumorigenesis.
NOTES
Supported by Yorkshire Cancer Research, the Breast Cancer Campaign and Cancer Research UK.
REFERENCES
(1) MacPherson G, Healey CS, Teare D, Balasubramanian S, Reed MW, Pharoah P, 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) The CHEK2-Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 2002;31:55–9.[CrossRef][Web of Science][Medline]
(3) Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N. Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 2004;96:434–42.
Related Correspondence
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2005 97: 1012.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||