|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2006.08.8229 on November 28 2006 © 2007 American Society of Clinical Oncology.
CHEK2 Mutation and Hereditary Breast Cancer
Centre for Research in Women's Health, Toronto, Ontario, Canada
Creighton University School of Medicine, Omaha, NE Two articles in the Journal of Clinical Oncology focus our attention on the presentation and clinical outcomes in women with breast cancer and a CHEK2 mutation.1,2 A recurrent mutation in the CHEK2 gene (1100delC) was first reported to be an important cause of breast cancer by Meijers-Heijboer et al3 in 2002. Since then, numerous studies have documented the prevalence of this single founder mutation in various populations, but until now few studies have reported on its clinical impact. Schmidt et al1 searched for the mutation in a cohort of 1,479 women from the Netherlands who had been treated for invasive breast cancer before the age of 50 years, and who were observed for a median of 10 years. The 1100delC germline mutation was identified in 54 patients (3.7%). In terms of pathology, CHEK2-associated tumors did not seem to be appreciably different from the mutation-negative tumors, although the women in the CHEK2 subgroup harbored a two-fold increased risk of developing a second primary breast cancer. In addition, when compared with noncarriers, the CHEK2 carriers also had a greater risk of cancer recurrence (hazard ratio, 2.1; P = .05) and a (nonsignificant) greater risk of breast cancer–specific mortality (hazard ratio, 1.4; P = .07). In a study from Denmark, Weischer et al2 documented this same 1100delC mutation in 13 of 1,088 breast cancer patients (1.2%) and in 0.5% of 9,231 Danish individuals from the general population. The reported excess breast cancer risk was about two-fold, but there were too few breast cancers to adequately characterize the pathologic features. The absolute incidence of breast cancer in CHEK2 mutation carriers was 390 per 100,000 per year, but this was based on only three incident cases (the cohort also was notable for increased risks of prostate and kidney cancers and of brain tumors).
The 1100delC mutation is even rarer in Poland (0.5% of unselected early-onset cases) than it is in the Netherlands (3.7%) or in Denmark (1.2%).4 However, Cybulski et al5 have identified two other protein-truncating founder CHEK2 mutations in Poland (del5395 and IVS2+1G Arguably, CHEK2 is the most important breast cancer susceptibility gene to be identified since BRCA2 was found in 1995. From these articles, and others, it is evident that that the contribution of CHEK2 mutations to the burden of breast cancer varies by ethnic group, and from country to country. The CHEK2*1100delC mutation appears to be most prevalent in the Netherlands (4% of patients with early-onset disease) and it is not surprising that scientists from this country continue to make important contributions to the CHEK2 literature. Similar high rates of mutations have been reported in studies from other Northern European countries, such as Finland6 (2.5% of patients) and Germany7 (2.3% of patients with early-onset disease). The 1100delC mutation is rare in Australia,8 in Spain,9 and in Ashkenazi Jews,10 but it is possible that other mutations will be found to be more relevant in these populations. The CHEK2 deletion, which was present in 1% of unselected breast cancer patients from Poland, was originally reported in multiple families of Czech and Slovak origin.11 CHEK2 has not been well studied in most ethnic groups. The data seem to be consistent, showing an increased risk for breast cancer in carriers of CHEK2 mutations that is roughly two-fold compared with noncarriers. Because of the rarity of mutations, it is unlikely that specific preventive trials will be undertaken for these high-risk women. For these women, the lifetime risk of breast cancer is approximately 15% to 20%, and few patients will consider prophylactic surgery at this level of risk. However, tamoxifen is an interesting prevention option. The majority of breast cancers in young women with BRCA1 mutations are ER negative, but this does not appear to be the case for CHEK2 carriers. In the Dutch study, 80% of the patients with CHEK2 mutations were ER positive,1 and in Poland, 65% of the patients with CHEK2 mutations were ER positive.4 However, it is an enormous challenge to evaluate a specific chemopreventive agent in such a small subgroup; based on the incidence rates reported in the article by Weischer et al,2 2,000 CHEK2 carriers would have to be observed for 5 years to document 40 new cancers (and we would have to identify and test 800,000 willing Danish women to find 4,000 carriers for randomization). Clearly, we must consider other strategies if we are to be successful in translating these basic scientific and epidemiologic discoveries into improved clinical care. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Steven A. Narod, Henry T. Lynch Administrative support: Henry T. Lynch Data analysis and interpretation: Steven A. Narod, Henry T. Lynch Manuscript writing: Steven A. Narod, Henry T. Lynch Final approval of manuscript: Steven A. Narod, Henry T. Lynch NOTES published online ahead of print at www.jco.org on November 27, 2006. REFERENCES
1. Schmidt MK, Tollenaar RAEM, 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 2. Weischer M, Bojesen SE, Tybjærg-Hansen A, et al: Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol 25: 57-63, 2007 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. Cybulski C, Gorski B, Huzarski T, et al: CHEK2-positive breast cancers in young Polish women. Clin Cancer Res 12:4832-4835, 2006 5. Cybulski C, Wokolorczyk D, Huzarski T, et al: A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat [epub ahead of print on August 8, 2006] 6. Kilpivaara O, Bartkova J, Eerola J, et al: Correlation of CHEK2 protein expression and 1100delC mutation status with tumor characteristics among unselected breast cancer patients. Int J Cancer 113:575-580, 2005[CrossRef][Medline] 7. Rashid MU, Jakubowska A, Justenhoven C: 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] 8. Jekimovs CR, Chen X, Arnold J, et al: Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families: Functional analysis in heterozygous individuals. Br J Cancer 92:784-790, 2005[CrossRef][Medline] 9. 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] 10. Offit K, Pierce H, Kirchhoff T, et al: Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 4:1, 2003[Medline] 11. Walsh T, Casadei S, Coats KH, et al: Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379-1388,2006
Related Correspondence
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
A) and, in total, the three mutations account for about 2.3% of all patients with early-onset disease. On the basis of a study of 47 early-onset CHEK2-positive patients, these authors conclude that CHEK2-positive patients are equally likely to be estrogen receptor (ER) positive as are patients with nonhereditary disease (65% and 64%, respectively), but they are more likely to have multicentric disease (29% v 20%) or have lobular histology (22% v 16%). Overall, there is not a characteristic CHEK2 signature.
