This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bogdanova, N. Articles by Dörk, T. Search for Related Content PubMed PubMed Citation Articles by Bogdanova, N. Articles by Dörk, T. Related Articles Related Articles Social Bookmarking                            What's this?

CHEK2 Mutation and Hereditary Breast Cancer

Department of Radiation Oncology, Hannover Medical School, Hannover, Germany

Sergei Feshchenko

Scientific-Practical Center "Mother and Child," Minsk, Belarus

Cezary Cybulski

Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland

Thilo Dörk

Department of Gynaecology and Obstetrics, Hannover Medical School, Hannover, Germany

To the Editor:

Two recent articles by Schmidt et al¹ and Weischer et al² provided compelling evidence that a truncating mutation in the CHEK2 gene, 1100delC, confers an about three-fold risk for breast cancer in the general Danish population and is associated with a worse breast cancer–specific survival in Dutch breast cancer patients. As addressed by Narod and Lynch³ in the accompanying editorial, 1100delC is only one of the truncating mutations that exist in the CHEK2 gene. A larger CHEK2 deletion spanning the exons 9 and 10 has been described as a Czech founder mutation⁴ and accounts for 0.9% of breast cancer patients in Poland,⁵ while it has not yet been studied in other ethnic groups.

We performed a breast cancer association study of two independent, hospital-based case-control series from Germany and from the Republic of Belarus, both of which had previously been tested for three other CHEK2 mutations (unpublished data). ^6,7 We screened for the presence of the CHEK2dele(9,10) mutation using a previously established allele-specific duplex polymerase chain reaction assay,⁵ and subsequently confirmed positive patients by long-range polymerase chain reaction.⁴ In the first study from Belarus, the CHEK2dele(9,10) allele was identified in 13 of 1,440 Byelorussian breast cancer patients (0.9%) but in none of 881 female control individuals (Yates’ corrected, P = .01). Three of 13 Byelorussian patients reported a first-degree family history, and one patient had bilateral disease. In the second study from Germany, the deletion was detected in five of 990 German breast cancer patients (0.5%) and in one of 1,014 female control individuals (0.1%; odds ratio, 5.1; 95% CI, 0.6 to 44.1; P = .2). Two of five German patients reported a first-degree family history of breast cancer, and one had metachronous bilateral disease. Altogether, the data indicate that the CHEK2dele(9,10) allele is associated with breast cancer (Mantel-Haenszel odds ratio, 15.2; 95% CI, 1.8 to 123.8; P = .002) and constitutes a significant risk factor in Central and Eastern Europe.

These findings confirm and expand the role of CHEK2 gene mutations in breast cancer susceptibility and suggest a need for studies addressing the clinical impact of CHEK2 mutations beyond 1100delC. A recent follow-up of CHEK2 mutation carriers at Hannover Medical School (Hannover, Germany) has provided suggestive evidence that the worse survival of CHEK2 heterozygous breast cancer patients may not be limited to carriers of the 1100delC mutation,⁸ but could be a more general feature of germ-line mutations in the CHEK2 gene. Larger studies of other common mutations, such as CHEK2dele(9,10), may prove helpful to further elucidate this issue and to finally translate the combined observations into improved clinical care.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

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[Abstract/Free Full Text]

2. Weischer M, Bojesen SE, Tybjorg-Hansen A, et al: Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol 25:57-63, 2007[Abstract/Free Full Text]

3. Narod SA, Lynch HT: CHEK2 mutation and hereditary breast cancer. J Clin Oncol 25:6-7, 2007[Free Full Text]

4. 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[Abstract/Free Full Text]

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 102:119-122, 2007[CrossRef][Medline]

6. The 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]

7. Bogdanova N, Enßen-Dubrowinskaja N, Feshchenko S, et al: Association of two mutations in the CHEK2 gene with breast cancer. Int J Cancer 116:263-266, 2005[CrossRef][Medline]

8. Meyer A, Dörk T, Sohn C, et al: Breast cancer in patients carrying a germ-line CHEK2 mutation: Outcome after breast conserving surgery and adjuvant radiotherapy. Radiother Oncol 82:349-353, 2007[CrossRef][Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Articles

• Increased Risk of Breast Cancer Associated With CHEK2*1100delC
  Maren Weischer, Stig Egil Bojesen, Anne Tybjærg-Hansen, Christen Kirk Axelsson, and Børge Grønne Nordestgaard
  JCO 2007 25: 57-63 [Abstract] [Full Text]
• CHEK2 Mutation and Hereditary Breast Cancer
  Steven A. Narod and Henry T. Lynch
  JCO 2007 25: 6-7 [Full Text]
• Breast Cancer Survival and Tumor Characteristics in Premenopausal Women Carrying the CHEK2*1100delC Germline Mutation
  Marjanka K. Schmidt, Rob A.E.M. Tollenaar, Sanne R. de Kemp, Annegien Broeks, Cees J. Cornelisse, Vincent T.H.B.M. Smit, Johannes L. Peterse, Flora E. van Leeuwen, and Laura J. Van 't Veer
  JCO 2007 25: 64-69 [Abstract] [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bogdanova, N. Articles by Dörk, T. Search for Related Content PubMed PubMed Citation Articles by Bogdanova, N. Articles by Dörk, T. Related Articles Related Articles Social Bookmarking                            What's this?