The CHEK2 I157T Variant and Breast Cancer Susceptibility: A Systematic Review and Meta-analysis

  • Published : 2012.04.30


Background: The cell cycle checkpoint kinase 2 (CHEK2) gene I157T variant may be associated with an increased risk of breast cancer, but it is unclear whether the evidence is sufficient to recommend testing for the mutation in clinical practice. Materials and Methods: We systematically searched PubMed, Embase, Elsevier and Springer for relevant articles published before Nov 2011. Summary odds ratio (OR) and 95% confidence interval (95% CI) incidence rates were calculated using a random-effects model with STATA (version 10.0) software. Results: A total of fifteen case-control studies, including 19,621 cases and 27,001 controls based on the search criteria, were included for analysis. A significant association was found between carrying the CHEK2 I157T variant and increased risk of unselected breast cancer (OR = 1.48, 95% CI = 1.31-1.66, P < 0.0001), familial breast cancer (OR = 1.48, 95% CI = 1.16-1.89, P < 0.0001), and early-onset breast cancer (OR = 1.47, 95% CI = 1.29-1.66, P < 0.0001). We found an even stronger significant association between the CHEK2 I157T C variant and increased risk of lobular type breast tumors (OR = 4.17, 95% CI = 2.89-6.03, P < 0.0001). Conclusion: Our research indicates that the CHEK2 I157T variant may be another important genetic mutation which increases risk of breast cancer, especially the lobular type.



  1. Allinen M, Huusko P, Mantyniemi S, et al (2001). Mutation analysis of the CHK2 gene in families with hereditary breast cancer. Br J Cancer, 85, 209-12.
  2. Ades AE, Lu G, Higgins JP (2005). The interpretation of randomeffects meta-analysis in decision models. Med Decis Making, 25, 646-54.
  3. Ahmedin J, Freddie B, Melissa M, et al (2011). Global Cancer Statistics. CA Cancer J Clin, 61, 69-90.
  4. Bell DW, Varley JM, Szydlo TE, et al (1999). Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science, 286, 2528-31.
  5. Bogdanova N, Enben-Dubrowinskaja N, Feshchenko S, et al (2005). Association of two mutations in the CHEK2 gene with breast cancer. Int J Cancer, 116, 263-6.
  6. Cochran WG (1954). The combination of estimates from different experiments. Biometrics, 10, 101-29.
  7. Collaborative Group on Hormonal Factors in Breast Cancer (2001). Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58, 209 women with breast cancer and 101,986 women without the disease. Lancet, 358, 1389-99.
  8. Cybulski C, Gorski B, Huzarski T, et al (2004). CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet, 75, 1131-5.
  9. Cybulski C, Gorski B, Huzarski T, et al (2006). CHEK2-Positive breast cancers in young Polish women. Clin Cancer Res, 12, 4832-5.
  10. Cybulski C, Wokołorczyk D, Huzarski T, et al (2007). A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat, 102, 119-22.
  11. Cybulski C, Gorski B, Huzarski T, et al (2009). Effect of CHEK2 missense variant I157T on the risk of breast cancer in carriers of other CHEK2 or BRCA1 mutations. J Med Genet, 46, 132-5.
  12. Cybulski C, Wokołorczyk D, Jakubowska A, et al (2011). Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol, 29, 3747-52.
  13. DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Control Clin Trials, 7, 177-88.
  14. Duvall S, Tweedie R (2000). A nonparametric "trim and fill" method for assessing publication bias in meta-analysis. J Am Stat Assoc, 95, 89-98.
  15. Dufault MR, Betz B, Wappenschmidt B, et al (2004). Limited relevance of the CHEK2 gene in hereditary breast cancer. Int J Cancer, 110, 320-5.
  16. Desjardins S, Belleau P, Labrie Y, et al (2008). Genetic variants and haplotype analyses of the ZBRK1/ZNF350 gene in high-risk non BRCA1/2 French Canadian breast and ovarian cancer families. Int J Cancer, 122, 108-16.
  17. Domagala P, Wokolorczyk D, Cybulski C, et al (2011). Different CHEK2 germline mutations are associated with distinct immunophenotypic molecular subtypes of breast cancer. Breast Cancer Res Treat, [Epub ahead of print].
  18. Egger M, Davey Smith G, Schneider M, et al (1997). Bias in meta-analysis detected by a simple, graphical test. Br Med J, 315, 629-34.
  19. Falck J, Mailand N, Syljuasen RG, et al (2001). The ATM-Chk2- Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature, 410, 842-7.
  20. Falck J, Lukas C, Protopopova M, et al (2001). Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway. Oncogene, 20, 5503-10.
  21. Falchetti M, Lupi R, Rizzolo P, et al (2008). BRCA1/BRCA2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases. Breast Cancer Res Treat, 110, 161-7.
  22. Gorski B, Cybulski C, Huzarski T, et al (2005). Breast cancer predisposing alleles in Poland. Breast Cancer Res Treat, 92, 19-24.
  23. Higgins JP, Thompson SG (2002). Quantifying heterogeneity in a meta-analysis. Stat Med, 21, 1539-58.
  24. Higgins JP, Thompson SG, Deeks JJ (2003), Altman DG. Measuring inconsistency in meta-analysis. BMJ, 327, 557-60.
  25. Huzarski T, Cybulski C, Domagała W, et al (2005). Pathology of breast cancer in women with constitutional CHEK2 mutations. Breast Cancer Res Treat, 90, 187-9.
  26. Kilpivaara O, Vahteristo P, Falck J, et al (2004). CHEK2 variant I157T may be associated with increased breast cancer risk. Int J Cancer, 111, 543-7.
  27. Kleib Z, Havranek O, Novotny J, et al (2008). Analysis of CHEK2 FHA domain in Czech patients with sporadic breast cancer revealed distinct rare genetic alterations. Breast Cancer Res Treat, 112, 159-64.
  28. Kaufman B, Laitman Y, Gronwald J, et al (2009). Haplotypes of the I157T CHEK2 germline mutation in ethnically diverse populations. Familial Cancer, 8, 473-8.
  29. Lee SB, Kim SH, Bell DW, et al (2001). Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni syndrome. Cancer Res, 61, 8062-7.
  30. Miki Y, Swensen J, Shattuck-Eidens D, et al (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science, 266, 66-71.
  31. Matsuoka S, Huang M, Elledge SJ (1998). Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science, 282, 1893-7.
  32. Meyer A, Dork T, Sohn C, et al (2007). Breast cancer in patients carrying a germ-line CHEK2 mutation: Outcome after breast conserving surgery and adjuvant radiotherapy. Radiother Oncol, 82, 349-53.
  33. McInerney NM, Miller N, Rowan A, et al (2010). Evaluation of variants in the CHEK2, BRIP1 and PALB2 genes in an Irish breast cancer cohort. Breast Cancer Res Treat, 121, 203-10.
  34. Narod SA, Foulkes WD (2004). BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer, 4, 665-76.
  35. Nevanlinna H, Bartek J (2006). The CHEK2 gene and inherited breast cancer susceptibility. Oncogene, 25, 5912-9.
  36. Novak DJ, Chen LQ, Ghadirian P, et al (2008). Identification of a novel CHEK2 variant and assessment of its contribution to the risk of breast cancer in French Canadian women. BMC Cancer, 8, 239.
  37. Schutte M, Seal S, Barfoot R, et al (2003). Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Am J Hum Genet, 72, 1023-8.
  38. Serrano-Fernandez P, Debniak T, Gorski B, et al (2009). Synergistic interaction of variants in CHEK2 and BRCA2 on breast cancer risk. Breast Cancer Res Treat, 117, 161-5.
  39. Sodha N, Mantoni TS, Tavtigian SV, et al (2006). Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation. Cancer Res, 66, 8966-70.
  40. Scharrer U, Skrzypczak-Zielinska M, Wituszynska W, et al (2010). A simple method of investigating mutations in CHEK2 by DHPLC: a study of the German populations of Saxony, Saxony-Anhalt and Thuringia. Cancer Genetics Cytogenetics, 199, 48-52.
  41. Vahteristo P, Tamminen A, Karvinen P, et al (2001). p53, Chk2, and Chk1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of Chk2 in inherited cancer predisposition. Cancer Res, 61, 5718-22.
  42. Wooster R, Bignell G, Lancaster J, et al (1995). Identification of the breast cancer susceptibility gene BRCA2. Nature, 378, 789-92.
  43. Weischer M, Bojesen E, Eilervik C, et al (2008). CHEK2*1100del genotyping for clinical assesment of breast cancer risk: metaanalyses of 26,000 patient cases and 27,000 controls. JCO, 26, 542-8.
  44. Wells GA, Shea B, O'Connell D, et al (1997). The Newcastle- Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses.

Cited by

  1. Non-random distribution of breast cancer susceptibility loci on human chromosomes vol.136, pp.1, 2012,
  2. Lack of CHEK2 Gene Mutations in Differentiated Thyroid Carcinoma Patients using High Resolution Melting Analysis vol.15, pp.12, 2014,
  3. The association between the APE1 Asp148Glu polymorphism and breast cancer susceptibility: a meta-analysis based on case–control studies vol.35, pp.5, 2014,
  4. CHEK2 represses breast stromal fibroblasts and their paracrine tumor-promoting effects through suppressing SDF-1 and IL-6 vol.16, pp.1, 2016,
  5. Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing vol.34, pp.34, 2016,
  6. An association study between CHEK2 gene mutations and susceptibility to breast cancer vol.26, pp.4, 2017,
  7. Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis vol.16, pp.4, 2017,
  8. Associations of pathogenic mutations responsible for breast cancer risk with histology and immunohistochemistry in Romanian population vol.26, pp.2, 2018,