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Journal of Clinical Oncology, Vol 26, No 18 (June 20), 2008: pp. 3092 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.9151
CHEK2 Screening: Do Not Think So Globally YetDepartment of Internal Medicine, Division of Hematology and Oncology, Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, MI To the Editor: We read with interest the article by Weischer et al1 and the corresponding Editorial2 published in Journal of Clinical Oncology addressing the role of the CHEK2*1100delC mutation in the risk for breast cancer. Weischer et al conclude that CHEK2*1100delC is an important breast cancer–predisposing mutation, which increases the risk of breast cancer three- to five-fold. We would like to clarify some of the results of this study, which we believe can be inappropriately interpreted. In the meta-analyses presented by Weischer et al,1 several subsets of patient characteristics, such as male sex, bilateral breast cancer, and non-European ethnicity, were not included. We believe that this exclusion may have biased and possibly resulted in assertions that are not fully founded by the evidence. In previously published articles, an important relationship was noted between CHEK2 mutation and male or bilateral breast cancer. The CHEK2 Breast Cancer Consortium3 study showed that the CHEK2*1100delC confers a 10-fold increase of breast cancer risk in men, compared with only a two-fold increase of breast cancer risk in women. Although other studies4 have failed to demonstrate those results, they have important limitations. Perhaps a more inclusive meta-analysis could help to better define the range of applicability of these results. Regarding bilateral breast cancer, Vahteristo et al5 observed that of a total of 33 patients with bilateral breast cancer, four (12.1%) carried the mutation, compared with 12 (2.0%) of the 594 patients with unilateral disease (odds ratio, 6.17; 95% CI, 1.87 to 20.32; P = .007). Likewise Broecks et al6 detected the CHEK2*1100delC variant in 6.4% (15 of 233) bilateral breast cancer patients and in 1% (two of 191) unilateral breast cancer patients (odds ratio, 6.5; 95% CI, 1.5 to 28.8; P = .005). Considering these results, it would have been really important to include in the meta-analyses information about bilaterality, to confirm or refute the strong association between CHEK2 and bilaterality. With regard to the ethnicity of the individuals included in the meta-analyses, we agree with the authors that including individuals with only Northern or Eastern European descent improves the homogeneity of the meta-analyses. However, it is important to notice that this restriction is also a limitation, given that the results are not applicable to other populations. Moreover, according with the literature, it is known that the prevalence of the mutation seems to be higher in those regions than in Southern Europe or North America, for example. These results then could help design new rational screening programs for breast cancer in high-risk individuals in these countries and to understand the prevalence of CHEK2*1100delC in other regions. However, at present, in the setting of counseling individual patients, these results are only applicable to Northern and Eastern Europeans. Finally, and most importantly, we point out a persistent problem in studies of inherited breast cancer, namely the "moving target" associated with the word "familial." Among all the studies included in the meta-analyses, one study7 considers breast cancer familial if the individual has at least two relatives with breast cancer, another8 considers at least three relatives familial, and a third3 counts one case of female breast cancer and one case or ovarian cancer or male breast cancer in the lineage as familial breast cancer. Moreover, one of the articles9 included in the study also classified female relatives with breast cancer according to menopausal status. Given the variation in entry criteria, we have doubts about the purported uniformity of the selection criteria for the population included in the meta-analyses, as stated by the authors. To conclude, in light of the limitations raised above, we strongly believe that based on data from previously published series, CHEK2*1100delC should not be genotyped upfront along with BRCA1/2 in individuals with a family history of breast cancer significant enough to warrant BRCA1/2 testing. The low incidence of the CHEK2*1100delC in the North American population limits its clinical relevance as a cancer-predisposing gene in this region; furthermore, this study does not apply to many ethnicities represented in North America. Studies with uniform inclusion criteria of family history are warranted to more accurately evaluate the importance of CHEK2*1100delC in North American individuals at high risk for breast or ovarian cancer. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS Supported by a grant from Fundacion Alfonso Martin Escudero, Madrid, Spain (M.D.I.). REFERENCES
1. Weischer M, Bojesen SE, Tybjaerg-Hansen A, et al: Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol 25:57-63, 2007 2. Offit K, Garber JE: Time to check CHEK2 in families with breast cancer? J Clin Oncol 26:519-520, 2008 3. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55-59, 2002[CrossRef][Medline] 4. Syrjäkoski K, Kuukasjarvi T, Auvinen A, et al: CHEK2 1100delC is not a risk factor for male breast cancer population. Int J Cancer 108:475-476, 2004[CrossRef][Medline] 5. Vahteristo P, Bartkova J, Eerola H, et al: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71:432-438, 2002[CrossRef][Medline] 6. Broeks A, de Witte L, Nooijen A, et al: Excess risk for contralateral breast cancer in CHEK2*1100delC germline mutation carriers. Breast Cancer Res Treat 83:91-93, 2004[CrossRef][Medline] 7. Sodha N, Bullock S, Taylor R, et al: CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours. Br J Cancer 87:1445-1448, 2002[CrossRef][Medline] 8. Rashid MU, Jakubowska A, Justenhoven C, et al: German populations with infrequent CHEK2*1100delC and minor associations with early-onset and familial breast cancer. Eur J Cancer 41:2896-2903, 2005[CrossRef][Medline] 9. Dufault MR, Betz B, Wappenschmidt B, et al: Limited relevance of the CHEK2 gene in hereditary breast cancer. Int J Cancer 110:320-325, 2004[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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