To the Editor: In their discussion of polygenics and breastcancer, Pharoah et al. (June 26 issue)1 do not mention cost-effectiveness.If we take 3% for the reduction in total disease burden estimatedby Pharoah et al. and apply it to the calculated 0.6-year increasein life expectancy if all breast cancers were eliminated,2 currentpolygenic tests would increase life expectancy by just 1 weekfor the whole female population.
Although the gain is modest, the relatively low cost of implementingthe polygenic approach makes it attractive when one considersthe estimated additional quality-adjusted life years (QALYs).Even a comprehensive genomewide scan incorporating 500,000 markersnow costs only $1,000,3 so using the figures for health-adjustedlife expectancy,2 one arrives at a cost of $67,000 per additionalQALY. This compares favorably with other approaches to improvingsurvival among patients with breast cancer4 and is certain tobecome more favorable as the cost of genome scanning plummets,more risk genes are documented, and many medical professionalsuse genome scans.
Richard J. Wilkins, Ph.D. University of Waikato Hamilton 3240, New Zealand d.wilkins{at}waikato.ac.nz
References
Pharoah PD, Antoniou AC, Easton DF, Ponder BA. Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 2008;358:2796-2803. [Free Full Text]
Manuel DG, Luo W, Ugnat A-M, Mao Y. Cause-deleted health-adjusted life expectancy of Canadians with selected chronic conditions. Chronic Dis Can 2003;24:108-115. [Medline]
Feero WG, Guttmacher AE, Collins FS. The genome gets personal -- almost. JAMA 2008;299:1351-1352. [Free Full Text]
Stout NK, Rosenberg MA, Trentham-Dietz A, Smith MA, Robinson SM, Fryback DG. Retrospective cost-effectiveness analysis of screening mammography. J Natl Cancer Inst 2006;98:774-782. [Free Full Text]
To the Editor: Pharoah et al. concluded "that genetic risk profileswould improve population-based programs of intervention forbreast cancer." They assumed that there are two copies of eachlocus in the genome and that the risk conferred by seven breast-cancersusceptibility alleles is allele-dose–dependent. Theyalso estimated the relative risk of breast cancer using a multiplicativemodel for interaction among seven common susceptibility alleles.However, they did not take into account the effect of copy-numbervariations. Moreover, three of seven alleles are located inregions of copy-number variations (http://projects.tcag.ca/variation/);for two of them, losses of copy in HapMap controls have beenidentified. Therefore, the number of possible combinations ishigher than estimated, and the relative risk should be reassessed.Copy-number variations have been shown to be associated withcommon disorders1 and to be responsible for variation in geneexpression.2 We would like to emphasize the difficulty of stratifyingpeople according to genetic risk and the complexity of integratingdifferent types of genetic variations in a statistical modelat present.
Luis Teixeira, M.D. Hôpital Saint-Louis 75010 Paris, France luis.teixeira{at}inserm.fr
Cedric Julien, Ph.D. INSERM Unité 567 75014 Paris, France
Fabien Guimiot, Ph.D. Hôpital Robert Debré 75019 Paris, France
References
Estivill X, Armengol L. Copy number variants and common disorders: filling the gaps and exploring complexity in genome-wide association studies. PLoS Genet 2007;3:1787-1799. [Web of Science][Medline]
Stranger BE, Forrest MS, Dunning M, et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 2007;315:848-853. [Free Full Text]
To the Editor: Pharoah et al. report on seven polymorphic markersfor breast-cancer risk replicated in genomewide-associationstudies. Although it is well known that cases of premenopausaland postmenopausal breast cancer have different risk factors,these cases were analyzed as one group. Polymorphisms may altergene expression, but expression is also regulated by environmentalfactors, which may lead to epigenetic changes.1 The magnitudeof risk modification may be miscalculated when premenopausaland postmenopausal patients are combined and no questionnairedata on relevant environmental risk factors are considered.For example, the protective effect of caffeinated coffee onhereditary and sporadic breast cancer appears to be substantialbut limited to women with the CYP1A2*1F C allele.2,3 CYP1A2is a key enzyme in caffeine and estrogen metabolism.4 It isbiologically plausible that various combinations of geneticand nongenetic factors (e.g., coffee) that regulate CYP1A2 expression5affect risk differently. Combining data from questionnairesand genomewide-association studies in which premenopausal andpostmenopausal patients are stratified may yield better riskestimates for the selection of women for screening.
Helena Jernström, Ph.D. Lund University SE-221 85 Lund, Sweden helena.jernstrom{at}med.lu.se
References
Waterland RA, Michels KB. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr 2007;27:363-388. [CrossRef][Web of Science][Medline]
Kotsopoulos J, Ghadirian P, El-Sohemy A, et al. The CYP1A2 genotype modifies the association between coffee consumption and breast cancer risk among BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev 2007;16:912-916. [Free Full Text]
Bågeman E, Ingvar C, Rose C, Jernström H. Coffee consumption and CYP1A2*1F genotype modify age at breast cancer diagnosis and estrogen receptor status. Cancer Epidemiol Biomarkers Prev 2008;17:895-901. [Free Full Text]
Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT. Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 2003;144:3382-3398. [Free Full Text]
Djordjevic N, Ghotbi R, Bertilsson L, Jankovic S, Aklillu E. Induction of CYP1A2 by heavy coffee consumption in Serbs and Swedes. Eur J Clin Pharmacol 2007;64:381-385. [CrossRef][Web of Science][Medline]
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