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. 2004 Oct;41(10):731–735. doi: 10.1136/jmg.2004.019737

Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant

G H de Bock 1, M Schutte 1, E Krol-Warmerdam 1, C Seynaeve 1, J Blom 1, C Brekelmans 1, H Meijers-Heijboer 1, C J van Asperen 1, C Cornelisse 1, P Devilee 1, R Tollenaar 1, J Klijn 1
PMCID: PMC1735606  PMID: 15466005

Abstract

Background: The germline CHEK2*1100delC variant has been associated with breast cancer in multiple case families where involvement of BRCA1 and BRCA2 has been excluded.

Methods: We have investigated the tumour characteristics and prognosis of carriers of this germline variant by means of a prospective cohort study in an unselected cohort of 1084 consecutive patients with primary breast cancer. Data were collected for 34 patients with a germline CHEK2*1100delC mutation and for 102 patients without this mutation, stratified by age and date of diagnosis of the first primary breast cancer (within 1 year).

Results: Carriers developed steroid receptor positive tumours (oestrogen receptor (ER): 91%; progesterone receptor (PR): 81%) more frequently than non-carriers (ER: 69%; PR: 53%; p = 0.04). Mutation carriers more frequently had a female first or second degree relative with breast cancer (p = 0.03), or had any first or second degree relative with breast or ovarian cancer (p = 0.04). Patients with the CHEK2 variant had a more unfavourable prognosis regarding the occurrence of contralateral breast cancer (relative risk (RR) = 5.74; 95% confidence interval (CI) 1.67 to 19.65), distant metastasis-free survival (RR = 2.81; 95% CI 1.20 to 6.58), and disease-free survival (RR = 3.86; 95% CI 1.91 to 7.78). As yet, no difference with respect to overall survival has been found at a median follow up of 3.8 years.

Conclusion: We conclude that carrying the CHEK2*1100delC mutation is an adverse prognostic indicator for breast cancer. If independently confirmed by others, intensive surveillance, and possibly preventive measures, should be considered for newly diagnosed breast cancer cases carrying the CHEK2*1100delC variant.

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Selected References

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  1. Antoniou A. C., Pharoah P. D. P., McMullan G., Day N. E., Stratton M. R., Peto J., Ponder B. J., Easton D. F. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer. 2002 Jan 7;86(1):76–83. doi: 10.1038/sj.bjc.6600008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bartek Jiri, Lukas Jiri. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 2003 May;3(5):421–429. doi: 10.1016/s1535-6108(03)00110-7. [DOI] [PubMed] [Google Scholar]
  3. Chappuis P. O., Rosenblatt J., Foulkes W. D. The influence of familial and hereditary factors on the prognosis of breast cancer. Ann Oncol. 1999 Oct;10(10):1163–1170. doi: 10.1023/a:1008301314812. [DOI] [PubMed] [Google Scholar]
  4. Chevallier B., Heintzmann F., Mosseri V., Dauce J. P., Bastit P., Graic Y., Brunelle P., Basuyau J. P., Comoz M., Asselain B. Prognostic value of estrogen and progesterone receptors in operable breast cancer. Results of a univariate and multivariate analysis. Cancer. 1988 Dec 15;62(12):2517–2524. doi: 10.1002/1097-0142(19881215)62:12<2517::aid-cncr2820621211>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  5. Cui J., Antoniou A. C., Dite G. S., Southey M. C., Venter D. J., Easton D. F., Giles G. G., McCredie M. R., Hopper J. L. After BRCA1 and BRCA2-what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer. Am J Hum Genet. 2000 Dec 27;68(2):420–431. doi: 10.1086/318187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Evans D. Gareth, Howell Anthony. Are BRCA1- and BRCA2-related breast cancers associated with increased mortality? Breast Cancer Res. 2004;6(1):E7–E7. doi: 10.1186/bcr748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Goode Ellen L., Dunning Alison M., Kuschel Bettina, Healey Catherine S., Day Nicholas E., Ponder Bruce A. J., Easton Douglas F., Pharoah Paul P. D. Effect of germ-line genetic variation on breast cancer survival in a population-based study. Cancer Res. 2002 Jun 1;62(11):3052–3057. [PubMed] [Google Scholar]
  8. Jack Melissa T., Woo Richard A., Motoyama Noboru, Takai Hitoyuki, Lee Patrick W. K. DNA-dependent protein kinase and checkpoint kinase 2 synergistically activate a latent population of p53 upon DNA damage. J Biol Chem. 2004 Jan 29;279(15):15269–15273. doi: 10.1074/jbc.M309917200. [DOI] [PubMed] [Google Scholar]
  9. Lakhani S. R., Jacquemier J., Sloane J. P., Gusterson B. A., Anderson T. J., van de Vijver M. J., Farid L. M., Venter D., Antoniou A., Storfer-Isser A. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst. 1998 Aug 5;90(15):1138–1145. doi: 10.1093/jnci/90.15.1138. [DOI] [PubMed] [Google Scholar]
  10. Meijers-Heijboer Hanne, Wijnen Juul, Vasen Hans, Wasielewski Marijke, Wagner Anja, Hollestelle Antoinette, Elstrodt Fons, van den Bos Renate, de Snoo Anja, Fat Grace Tjon A. The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet. 2003 Apr 10;72(5):1308–1314. doi: 10.1086/375121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Oldenburg Rogier A., Kroeze-Jansema Karin, Kraan Jaennelle, Morreau Hans, Klijn Jan G. M., Hoogerbrugge Nicoline, Ligtenberg Marjolein J. L., van Asperen Christi J., Vasen Hans F. A., Meijers Carel. The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res. 2003 Dec 1;63(23):8153–8157. [PubMed] [Google Scholar]
  12. Pharoah Paul D. P., Antoniou Antonis, Bobrow Martin, Zimmern Ron L., Easton Douglas F., Ponder Bruce A. J. Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet. 2002 Mar 4;31(1):33–36. doi: 10.1038/ng853. [DOI] [PubMed] [Google Scholar]
  13. Phillips K. A., Andrulis I. L., Goodwin P. J. Breast carcinomas arising in carriers of mutations in BRCA1 or BRCA2: are they prognostically different? J Clin Oncol. 1999 Nov;17(11):3653–3663. doi: 10.1200/JCO.1999.17.11.3653. [DOI] [PubMed] [Google Scholar]
  14. Robson M. Are BRCA1- and BRCA2-associated breast cancers different? Prognosis of BRCA1-associated breast cancer. J Clin Oncol. 2000 Nov 1;18(21 Suppl):113S–118S. [PubMed] [Google Scholar]
  15. Vahteristo Pia, Bartkova Jirina, Eerola Hannaleena, Syrjäkoski Kirsi, Ojala Salla, Kilpivaara Outi, Tamminen Anitta, Kononen Juha, Aittomäki Kristiina, Heikkilä Päivi. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002 Jul 28;71(2):432–438. doi: 10.1086/341943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Verhoog L. C., Berns E. M., Brekelmans C. T., Seynaeve C., Meijers-Heijboer E. J., Klijn J. G. Prognostic significance of germline BRCA2 mutations in hereditary breast cancer patients. J Clin Oncol. 2000 Nov 1;18(21 Suppl):119S–124S. [PubMed] [Google Scholar]
  17. Verhoog L. C., Brekelmans C. T., Seynaeve C., van den Bosch L. M., Dahmen G., van Geel A. N., Tilanus-Linthorst M. M., Bartels C. C., Wagner A., van den Ouweland A. Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet. 1998 Jan 31;351(9099):316–321. doi: 10.1016/s0140-6736(97)07065-7. [DOI] [PubMed] [Google Scholar]
  18. de Bock G. H., Tollenaar R. A., Papelard H., Cornelisse C. J., Devilee P., van de Vijver M. J. Clinical and pathological features of BRCA1 associated carcinomas in a hospital-based sample of Dutch breast cancer patients. Br J Cancer. 2001 Nov 2;85(9):1347–1350. doi: 10.1054/bjoc.2001.2103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. de Jong M. M., Nolte I. M., te Meerman G. J., van der Graaf W. T. A., Oosterwijk J. C., Kleibeuker J. H., Schaapveld M., de Vries E. G. E. Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility. J Med Genet. 2002 Apr;39(4):225–242. doi: 10.1136/jmg.39.4.225. [DOI] [PMC free article] [PubMed] [Google Scholar]

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