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Originally published as JCO Early Release 10.1200/JCO.2007.13.8503 on January 2 2008 © 2008 American Society of Clinical Oncology.
Time to Check CHEK2 in Families With Breast Cancer?
Memorial Sloan-Kettering Cancer Center, New York, NY
Dana Farber Cancer Institute, Boston, MA CHEK2 (cell cycle checkpoint kinase 2) is an important player in the team of all-stars implicated in DNA repair and human cancer predisposition, including BRCA1, BRCA2/FANCD2, TP53, and ATM. CHEK2 is a serine threonine kinase that is activated by ATM protein in response to DNA double-strand breaks. CHEK2 not only regulates the function of BRCA1 protein in DNA repair but also exerts a number of critical roles in cell cycle control and apoptosis.1 The patterns of cancer risk associated with germline mutations in the critical genes in BRCA-associated DNA repair are remarkably variable. For example, PALB2, a recently identified BRCA2-interacting protein and a key player in the BRCA1-BRCA2 biochemical complex, appears to be rarely mutated in families with multiple patient cases of early-onset breast cancer.2 For ATM, however, the paucity of high-penetrance mutations has been a continuing puzzle.3 One particular CHEK2 mutation, 1100delC in exon 10, which abolishes its kinase function, has been evaluated in numerous reports because of its association with breast and other cancers in both unselected and familial breast cancer cohorts.4 Other CHEK2 mutations have been evaluated in vitro and in vivo and have shown diminished CHEK2 function and population specificity but no clear relationship to breast cancer risk.5 In this issue of the Journal of Clinical Oncology, Weischer et al6 attempt to provide more stable estimates of the breast cancer risk associated with CHEK2*1100C, and, on the basis of these estimates, raise a challenge: Are we ready to consider screening for this mutation as part of the clinical evaluation of families with breast cancers? To address this challenge, it is instructive to examine the insights and the limitations afforded by the many studies included in the meta-analysis of this particular cancer-predisposing mutation. Both family-based (genetic) and population-based epidemiologic methodologies have been employed to determine the cancer spectrum (phenotype), risk (penetrance), number of individual mutations (allelic heterogeneity), and distribution of mutations in different geographic groups (population heterogeneity) associated with candidate cancer predisposition genes, such as CHEK2. Turning first to the issue of phenotype, what is the cancer spectrum associated with CHEK2*1100C? Weischer et al6 focus appropriately on breast cancer. However, CHEK2*1100delC was initially described in a kindred with classic Li-Fraumeni syndrome; two carriers had breast cancer, but the third had a histiocytoma.7 In a multicenter study of cancer incidence in 67 families with at least one CHEK2*1100C mutation carrier, the risk of cancers other than breast was not significantly elevated, except for colorectal and lung cancers in women aged 20 to 50 years. No excess of cancer was observed in male relatives, though underreporting was demonstrated.8 Others have observed increases in breast cancer in men and in colorectal and prostate cancers, but these have not been characterized with the same level of detail as the breast cancer risk in women. The next critical question is whether CHEK2*1100delC is really a low penetrance mutation. In their meta-analysis, Weischer et al6 calculated a cumulative breast cancer risk by age 70 years in families with breast cancer of 37% (95% CI, 26% to 56%) for the 1100delC allele. They consider this comparable to the recently reported 57% (95% CI, 47% to 66%) penetrance for BRCA1 and 49% (95% CI, 40% to 57%) for BRCA2.9 Several caveats should be considered in this context. First, the upper band of the risk estimate in the meta-analysis by Weischer et al4 is derived from nine studies of patients with familial breast cancer. The methods of ascertainment for these studies varied widely, and at least one was population-based.1 Several of these studies utilized ascertainments that selected for familial clustering of breast cancer, and a range of criteria was used to define "familial."1,10-12 Of note, the BRCA meta-analysis cited by Weischer et al explicitly sought to limit its scope to exclude familial patient cases and to limit to population-based ascertainments.9 Thus, comparison of the BRCA population-based risk estimates and the CHEK2*1100delC familial-based penetrance estimates runs the risk of what Weischer et al4 call the apples and oranges dilemma. Attention to the type of studies included in these meta-analyses is important because of the now well-established appreciation that selected ascertainments appear to create a bias toward high penetrance estimates.13 The degree to which penetrance estimates vary for BRCA1 and BRCA2 remains a topic of intense controversy among cancer epidemiologists; explanations for the differences in risk estimates among studies include the biases in patient case (and control) ascertainment resulting from selective participation or other methodologic factors, the differing environmental or other modifying genetic factors, and genotype-phenotype associations that affect kindreds segregating BRCA mutations.14 In the subset analysis by Weischer et al,6 using study designs least prone to ascertainment bias (ie, unselected breast cancer cases), the aggregated odds ratio for breast cancer was 2.7, and this dropped to 1.8 (95% CI, 1.2 to 2.5) when the two largest studies were excluded.15,16 One of these large studies was published earlier this year in JCO by this same group.15 In that study, only 13 1100delC mutation carriers were identified in more than 1,000 breast cancer patient cases, which gives a broad confidence for the observed risk of 1.3 to 5.4. Another consideration in all genetic studies of this type is population heterogeneity, which is the result of different mutations having different frequencies in groups of varying geographic (and presumably genetic) origin. CHEK2 is a good example of this phenomenon. In the populations where it is most prevalent (Northern and Eastern Europe), CHEK2*1100delC is seen in 1 of 100 to 1 of 200 individuals. In North America, the frequency is only 1 of 333 to 1 of 5001,17,18; it is virtually absent in Spain and India.19,20 Thus, testing for CHEK2*1100C will have the highest yield in such regions as the Netherlands, Finland, and Denmark, where the allele is the most frequent. Similarly, in other populations, other CHEK2 mutations may emerge; for example CHEK2*S428F is observed in Ashkenazi Jews,21 although the CHEK2*1100C is rare.17 A particularly vexing challenge to the integration of CHEK2 testing into routine clinical practice is its variable penetrance and the presence of phenocopies. Phenocopies are individuals with the appearance of a hereditary cancer but who, in fact, carry no predisposing mutation. In addition, individuals may harbor a low-penetrance mutation but may never develop cancer. The occurrence of variable penetrance combined with the complexities of genetic heterogeneity (ie, multiple genes associated with hereditary breast cancer) suggest that clinical application of CHEK2 genotyping is not yet routinely at hand. The concern is that patients with mutations such as CHEK2*1100delC may seek unnecessary interventions (eg, preventive surgery) and that those without the mutation may feel false reassurance. The challenges posed by CHEK2*1100delC force us to confront the issues that will continue to arise in considering whether, when, and how to incorporate the increasing array of cancer risk markers into clinical care. CHEK2 researchers have provided copious epidemiologic and laboratory data. The 1100delC mutation, although technically easy to assay, is rare. This rarity also limits the ability to define the clinical syndrome and to precisely estimate penetrance, particularly in families with cancer, in which biases exert strong effects. Meta-analysis is one technique with which to overcome such difficulties, yet, even here, the pooled results in familial breast cancer provided fewer than 200 mutation carriers. Rarity also serves as a barrier for prospective prevention trials for CHEK2 mutation carriers, whose breast cancers are greater than 90% hormone receptor–positive and therefore potentially are amenable to a hormonal intervention.22 It has been estimated that 800,000 women would need to be screened to identify 4,000 women for random assignment onto a 5-year trial in Denmark.23 The emerging challenge in preventive oncology, now that testing for high-risk BRCA mutations has been integrated into practice, is how to rationally incorporate the rare variants associated with high risk, such as PALB2; the rare variants associated with low to intermediate risk, such as CHEK2; and the emerging panoply of common alleles associated with low risk, such as FGFR2 and other variants that emerged from whole genome association studies.24 On the basis of data available at the present time, we do not feel that there is compelling evidence to justify routine clinical testing for CHEK2*1100C to guide the management of families affected with breast cancer. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Kenneth Offit, Judy Ellen Garber Manuscript writing: Kenneth Offit, Judy Ellen Garber Final approval of manuscript: Kenneth Offit, Judy Ellen Garber NOTES published online ahead of print at www.jco.org on January 2, 2008 REFERENCES
1. Bernstein JL, Teraoka SN, John EM, et al: The CHEK2*1100delC allelic variant and risk of breast cancer: Screening results from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev 15:348-352, 2006 2. Tischkowitz M, Xia B, Sabbaghian N, et al: Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci USA 104:6788-6793, 2007 3. Ahmed M, Rahman N: ATM and breast cancer susceptibility. Oncogene 25:5906-5911, 2006[CrossRef][Medline] 4. Nevanlinna H, Bartek J: The CHEK2 gene and inherited breast cancer susceptibility. Oncogene 25:5912-5919, 2006[CrossRef][Medline] 5. Bell DW, Kim SH, Godwin AK, et al: Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts. Int J Cancer 121:2661-2667, 2007[CrossRef][Medline] 6. Weischer M, Bojesen SE, Ellervik C, et al: CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: Meta-analysis of 26,000 patient cases and 27,000 controls. J Clin Oncol 26:542-548, 2008 7. Bell DW, Varley JM, Szydlo TE, et al: Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286:2528-2531, 1999 8. Thompson D, Seal S, Schutte M, et al: A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer Epidemiol Biomarkers Prev 15:2542-2545, 2006 9. Chen S, Parmigiani G: Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25:1329-1333, 2007 10. 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] 11. 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] 12. Rashid MU, Jakubowksa 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] 13. Begg CB: On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer Inst 94:1221-1226, 2002 14. Offit K: BRCA mutation frequency and penetrance: New data, old debate. J Natl Cancer Inst 98:1675-1677, 2006 15. 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 16. CHEK2 Breast Cancer Case-Control Consortium: CHEK2*1100delC and susceptibility to breast cancer: A collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 74:1175-1182, 2004[CrossRef][Medline] 17. Offit K, Pierce H, Kirchhoff T, et al: Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 15:4:1, 2003 18. Friedrichsen DM, Malone KE, Doody DR, et al: Frequency of CHEK2 mutations in a population based, case-control study of breast cancer in young women. Breast Cancer Res 6:R629-R635, 2004[CrossRef][Medline] 19. Osorio A, Rodriguez-Lopez R, Diez O, et al: The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer 108:54-56, 2004[CrossRef][Medline] 20. Rajkumar T, Soumittra N, Nancy NK, et al: BRCA1, BRCA2 and CHEK2 (1100 del C) germline mutations in hereditary breast and ovarian cancer families in South India. Asian Pac J Cancer Prev 4:203-208, 2003[Medline] 21. Shaag A, Walsh T, Renbaum P, et al: Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet 14:555-563, 2005 22. Schmidt MK, Tollenaar RA, de Kemp SR, et al: Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. J Clin Oncol 25:64-69, 2007 23. Narod SA, Lynch HT: CHEK2 mutation and hereditary breast cancer. J Clin Oncol 25:6-7, 2007 24. Easton DF, Pooley KA, Dunning AM, et al: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087-1093, 2007[CrossRef][Medline] Related Article
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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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