Short Report

You have full text access to this OnlineOpen article

CHEK2 1100delC is not a risk factor for male breast cancer population

  1. Kirsi Syrjäkoski1,
  2. Tuula Kuukasjärvi2,†,*,
  3. Anssi Auvinen3,
  4. Olli-P Kallioniemi1

Article first published online: 21 OCT 2003

DOI: 10.1002/ijc.11384

Issue

International Journal of Cancer

International Journal of Cancer

Volume 108, Issue 3, pages 475–476, 20 January 2004

Additional Information

How to Cite

Syrjäkoski, K., Kuukasjärvi, T., Auvinen, A. and Kallioniemi, O.-P. (2004), CHEK2 1100delC is not a risk factor for male breast cancer population. Int. J. Cancer, 108: 475–476. doi: 10.1002/ijc.11384

Author Information

  1. 1

    Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland

  2. 2

    Department of Pathology, Tampere University Hospital, Tampere, Finland

  3. 3

    Tampere School of Public Health, University of Tampere, Tampere, Finland

  1. †

    Fax: +358-3-247 5503

*Department of Pathology, Tampere University Hospital, P.O. Box 2000, FIN-33521 Tampere, Finland

Publication History

  1. Issue published online: 21 NOV 2003
  2. Article first published online: 21 OCT 2003
  3. Manuscript Accepted: 5 DEC 2002
  4. Manuscript Received: 8 NOV 2002

Funded by

  • Research Fund of Tampere University Hospital

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

Get PDF (50K)

Keywords:

  • male breast cancer;
  • CHEK2;
  • germline mutation

Abstract

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS AND DISCUSSION
  5. Acknowledgements
  6. REFERENCES

Genetic risk factors for male breast cancer (MBC) are poorly understood. High penetrance genes such as BRCA1 or BRCA2 account for only a small proportion of the disease. A 1100delC mutation in CHEK2 (previously known as CHK2), a cell-cycle checkpoint kinase, has been implicated in predisposition of Li-Fraumeni syndrome (LFS) and breast cancer in families suggestive of LFS. This 1100delC mutation has also been shown to confer a 2-fold increase of breast cancer risk in women and a 10-fold increase of risk in men. It was estimated to account for 1% of breast cancers in women and as much as 9% of breast cancers in men at the population level based on analysis of breast cancer families without BRCA1 or BRCA2 mutations. We wanted to evaluate the significance of CHEK2 1100delC in predisposition to MBC by assessing its frequency in a population-based material of 114 Finnish MBC patients. Two patients (1.8%) carried the 1100delC mutation. The mutation frequency among MBC cases was similar to that seen in population controls (26/1885, 1.4%). Our results indicate that CHEK2 1100delC variant does not substantially increase the risk of male breast cancer at the population level. We cannot exclude the fact that a small fraction of hereditary, family-positive male breast cancers could be attributable to CHEK2 mutations. © 2003 Wiley-Liss, Inc.

The etiology of male breast cancer (MBC) is poorly understood. The strongest genetic risk factor is a germ-line mutation in the BRCA2 tumor suppressor gene. BRCA2 mutation frequencies vary greatly (4–40%) among different MBC populations.1, 2, 3 In Finland 7.8% (12/154) of unselected MBC cases in a nation-wide, population-based cohort carried a BRCA2 mutation (Syrjäkoski, article in preparation). BRCA2 mutation spectrum of MBC cases differed from that of the unselected female breast cancer patients, suggesting possible involvement of modifying factors.4 It has been suggested that a substantial proportion of male breast cancers are attributable to genetic factors.3, 5 Therefore, the low frequency of BRCA2 mutations in Finnish MBC patients suggests that other etiological factors may be involved.

CHEK2 (previously known as CHK2), a human homolog of budding yeast Cds1 and fission yeast Rad53, is a cell-cycle checkpoint kinase that mediates cellular responses to DNA damage.6, 7 CHEK2 acts downstream of ataxia teleangiectasia mutated (ATM) in the p53-pathway, leading to cell cycle arrest at G1.8, 9, 10 In response to double-strand DNA breaks, CHEK2 activates p53 by phosphorylation.8, 10 CHEK2 also regulates the function of BRCA1 protein after DNA damage.11

A protein truncating mutation 1100delC in exon 10, abolishing the kinase function of CHEK2, has been found in Li-Fraumeni syndrome (LFS) and breast cancer families suggestive of LFS.12, 13 CHEK2 1100delC variant has also been shown to confer an approximately 2-fold increase of breast cancer risk in women and a 10-fold increase of risk in men lacking BRCA1 and BRCA2 mutations.14 This mutation was reported to account for 1% of breast cancers in women and as much as 9% of breast cancers in men.14

Recently we studied the frequency of this mutation in an unselected population-based cohort and in an independent cohort of familial breast cancer patients.15 Frequency of 1100delC was elevated in breast cancer patients with a positive family history as compared to population controls. Patients with bilateral breast cancer were over 6-fold more likely to be 1100delC carriers than controls.

Here, we evaluated the contribution of CHEK2 1100delC in predisposition to MBC by assessing its frequency in a population-based cohort of 114 MBC patients.

ATM, ataxia teleangiectasia mutated; CHEK2, cell-cycle checkpoint kinase 2; FBC, female breast cancer; LFS, Li-Fraumeni syndrome; MBC, male breast cancer.

MATERIAL AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS AND DISCUSSION
  5. Acknowledgements
  6. REFERENCES

We identified all 237 MBC patients diagnosed in Finland between 1967 and 1996 from the Finnish Cancer Registry. First- and second-degree relatives were identified from the population registry and from the church records, when available. Incident cancer cases among these relatives were identified through a record-linkage with the Cancer Registry. The study protocol was approved by the Ethical Committee of the Tampere University Hospital and the Ministry of Social Affairs and Health in Finland.

Seventy-nine patients (33%) were alive and were approached by their attending hospitals. Thirty-seven patients responded to the invitation to participate. A written, informed consent and a blood sample were obtained and the patient was asked to fill in a questionnaire on family history of cancers. Paraffin-embedded tissue samples with confirmed breast cancer diagnosis were obtained for additional 122 patients. Of the paraffin samples, 77 provided sufficient amount and quality of DNA and were included into the study.

All the 114 patients had been screened for previously found Finnish BRCA2 mutations (Syrjäkoski, article in preparation). Four different germline mutations were found: 9346(-2)A>G in 6 patients and 999del5, 4075delGT, 5808del5 and 7708C>T in 1 patient each.

Mutation detection of CHEK2 1100delC was done using solid-phase minisequencing.16 Mutation positive and negative controls as well as a negative control for the PCR reaction were included in each detection. Since the DNA sequence containing exon 10 of CHEK2 is present in multiple homologous copies in the genome, specific PCR primers for the CHEK2 exon 10 on chromosome 22 were designed.

RESULTS AND DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS AND DISCUSSION
  5. Acknowledgements
  6. REFERENCES

Two of the 114 Finnish MBC patients (1,8%) carried the 1100delC mutation. The mutation frequency among MBC cases was similar to that seen in population controls in a previous study (26/1885, 1,4%),15 corresponding to a prevalence ratio of 1.27 (exact 95% confidence interval 0.04–7.92).

Among the relatives of 114 MBC patients, female breast cancer (FBC) was reported in 9 families, ovarian cancer in 1 family and FBC, MBC and ovarian cancer in 2 families. The 2 1100delC allele carriers did not have a positive family history of cancer.

In a recent study, a much higher frequency of the 1100delC mutation (7/52, 13,5%) was reported among individuals from MBC families.14 The difference in mutation frequencies among MBC patients could be explained by selection of subjects. We were able to include in our analyses approximately half of all male breast cancer patients diagnosed in Finland during the study period. The study subjects were selected only on the basis of sufficient amount and quality of DNA available, including only 12 patients with family history of breast or ovarian cancer (12/114, 10,5%). The CHEK2-Consortium14 analyzed breast cancer patients from families without BRCA1 or BRCA2 mutations who had at least 1 case of female and 1 case of male breast cancer in first- or second-degree relatives. There was not a great difference in frequencies in their (18/1620, 1,1%) and in the Finnish control populations.14, 15

The mean age at breast cancer diagnosis among the 114 patients was 65.1 years (standard deviation 12.9; range 30–94). The 2 carriers of the 1100delC were diagnosed with breast cancer at the ages of 66 and 67 years. Therefore, CHEK2 1100delC did not seem to influence the age of breast cancer onset.

One of the 6 (16,7%) BRCA2 9346(-2)A>G mutation positive case carried also the CHEK2 1100delC variant. In a cohort of 1035 unselected Finnish breast cancer patients, none of the 21 CHEK2 positive cases carried a BRCA1 or BRCA2 mutation.15 These studies suggest that CHEK2 1100delC mutation is usually independent of BRCA1 and BRCA2 mutations.

In conclusion, our results indicate that CHEK2 1100delC variant does not significantly increase the risk of male breast cancer at the population level. The frequency of the germline mutation is <2% in male breast cancer patients. However, we cannot exclude the fact that a small fraction of hereditary, family-positive male breast cancers could be attributable to CHEK2.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS AND DISCUSSION
  5. Acknowledgements
  6. REFERENCES

We wish to thank families and attending doctors participating in the study and Kati Rouhento for technical assistance.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS AND DISCUSSION
  5. Acknowledgements
  6. REFERENCES
  • 1
    Friedman LS, Gayther SA, Kurosaki T, Gordon D, Noble B, Casey G, Ponder BA, Anton-Culver H. Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. Am J Hum Genet 1997; 60: 313–9.
  • 2
    Couch FJ, Farid LM, DeShano ML, Tavtigian SV, Calzone K, Campeau L, Peng Y, Bogden B, Chen Q, Neuhausen S, Shattuck-Eidens D, Godwin AK, et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet 1996; 13: 123–5.
  • 3
    Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, Tulinius H, Ogmundsdottir HM, Eyfjord JE. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet. 1996; 13: 117–9.
  • 4
    Syrjäkoski K, Vahteristo P, Eerola H, Tamminen A, Kivinummi K, Sarantaus L, Holli K, Blomqvist C, Kallioniemi OP, Kainu T, Nevanlinna H. Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients. J Natl Cancer Inst 2000; 92: 1529–31.
  • 5
    Rosenblatt KA, Thomas DB, McTiernan A, Austin MA, Stalsberg H, Stemhagen A, Thompson WD, Curnen MG, Satariano W, Austin DF. Breast cancer in men: aspects of familial aggregation. J Natl Cancer Inst 1991; 83: 849–54
  • 6
    Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature 2000; 408: 433–9.
  • 7
    Bartek J, Falck J, Lukas J. CHK2 kinase: a busy messenger. Nat Rev Mol Cell Biol 2001; 2: 877–86.
  • 8
    Chehab NH, Malikzay A, Appel M, Halazonetis TD. Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev 2000; 14: 278–88
  • 9
    Kastan MB, Lim DS. The many substrates and functions of ATM. Nat Rev Mol Cell Biol 2000; 1: 179–86.
  • 10
    Shieh SY, Ahn J, Tamai K, Taya Y, Prives C. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 2000; 14: 289–300.
  • 11
    Lee JS, Collins KM, Brown AL, Lee CH, Chung JH. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 2000; 404: 201–4.
  • 12
    Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 1999; 24;286: 2528–31.
  • 13
    Vahteristo P, Tamminen A, Karvinen P, Eerola H, Eklund C, Aaltonen LA, Blomqvist C, Aittomäki K, Nevanlinna H. p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res 2001; 61: 5718–22.
  • 14
    Meijers-Heijboer H, van Den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, et al. Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 2002 Published online, DOI:10.1038/ng879; 31: 55–59.
  • 15
    Vahteristo P, Bartkova J, Eerola H, Syrjäkoski K, Ojala S, Kilpivaara O, Tamminen A, Kononen J, Aittomäki K, Heikkilä P, Holli K, Blomqvist C, et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 2002; 71: 432–8.
  • 16
    Syvänen AC. Solid-phase minisequencing as a tool to detect DNA polymorphism. Methods Mol Biol 1998; 98: 291–8.
Get PDF (50K)