CHEK2 Mutation and HereditaryBreast Cancer

TO THE EDITOR: Two recent articles by Schmidt et al1 andWeischer et al2 provided compelling evidence that a truncating muta-tion in the CHEK2 gene, 1100delC, confers an about three-fold risk forbreast cancer in the general Danish population and is associated with aworse 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 theCHEK2 gene. A larger CHEK2 deletion spanning the exons 9 and 10has been described as a Czech founder mutation4 and accounts for0.9% of breast cancer patients in Poland,5 while it has not yet beenstudied in other ethnic groups.

We performed a breast cancer association study of two indepen-dent, hospital-based case-control series from Germany and from theRepublic of Belarus, both of which had previously been tested for threeother CHEK2 mutations (unpublished data). 6,7 We screened for thepresence of the CHEK2dele(9,10) mutation using a previously estab-lished allele-specific duplex polymerase chain reaction assay,5 andsubsequently confirmed positive patients by long-range polymerasechain 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-degreefamily history, and one patient had bilateral disease. In the secondstudy from Germany, the deletion was detected in five of 990 Germanbreast cancer patients (0.5%) and in one of 1,014 female controlindividuals (0.1%; odds ratio, 5.1; 95% CI, 0.6 to 44.1; P � .2). Two offive German patients reported a first-degree family history ofbreast cancer, and one had metachronous bilateral disease. Alto-gether, the data indicate that the CHEK2dele(9,10) allele is associ-ated with breast cancer (Mantel-Haenszel odds ratio, 15.2; 95% CI,1.8 to 123.8; P � .002) and constitutes a significant risk factor inCentral and Eastern Europe.

These findings confirm and expand the role of CHEK2 genemutations in breast cancer susceptibility and suggest a need forstudies addressing the clinical impact of CHEK2 mutations beyond1100delC. A recent follow-up of CHEK2 mutation carriers at Han-nover Medical School (Hannover, Germany) has provided sugges-

tive evidence that the worse survival of CHEK2 heterozygous breastcancer patients may not be limited to carriers of the 1100delCmutation,8 but could be a more general feature of germ-line mu-tations in the CHEK2 gene. Larger studies of other common mu-tations, such as CHEK2dele(9,10), may prove helpful to furtherelucidate this issue and to finally translate the combined observa-tions into improved clinical care.

Natalia BogdanovaDepartment of Radiation Oncology, Hannover Medical School, Hannover, Germany

Sergei FeshchenkoScientific-Practical Center “Mother and Child,” Minsk, Belarus

Cezary CybulskiDepartment of Genetics and Pathology, International Hereditary CancerCenter, Pomeranian Medical University, Szczecin, Poland

Thilo DörkDepartment of Gynaecology and Obstetrics, Hannover Medical School,Hannover, Germany

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe author(s) indicated no potential conflicts of interest.

REFERENCES1. Schmidt MK, Tollenaar RAEM, de Kemp SR, et al: Breast cancer survival and

tumor characteristics in premenopausal women carrying the CHEK2*1100delCgermline mutation. J Clin Oncol 25:64-69, 2007

2. Weischer M, Bojesen SE, Tybjorg-Hansen A, et al: Increased risk of breastcancer associated with CHEK2*1100delC. J Clin Oncol 25:57-63, 2007

3. Narod SA, Lynch HT: CHEK2 mutation and hereditary breast cancer. J ClinOncol 25:6-7, 2007

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. JAMA295:1379-1388, 2006

5. Cybulski C, Wokolorczyk D, Huzarski T, et al: A deletion in CHEK2 of 5,395bp predisposes to breast cancer in Poland. Breast Cancer Res Treat 102:119-122,2007

6. The CHEK2 Breast Cancer Case-Control Consortium: CHEK2*1100delC andsusceptibility to breast cancer: A collaborative analysis involving 10,860 breastcancer cases and 9,065 controls from 10 studies. Am J Hum Genet 74:1175-1182, 2004

7. Bogdanova N, En�en-Dubrowinskaja N, Feshchenko S, et al: Association oftwo mutations in the CHEK2 gene with breast cancer. Int J Cancer 116:263-266,2005

8. Meyer A, Dörk T, Sohn C, et al: Breast cancer in patients carrying agerm-line CHEK2 mutation: Outcome after breast conserving surgery andadjuvant radiotherapy. Radiother Oncol 82:349-353, 2007

DOI: 10.1200/JCO.2007.11.4223

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JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E

VOLUME 25 � NUMBER 19 � JULY 1 2007

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