Identification of a Novel BRCA2 and CHEK2 A-C-G-C Haplotype in Turkish Patients Affected with Breast Cancer

  • Haytural, Hazal (Department of Neuroscience, Institute for Experimental Medicine Research, Istanbul University) ;
  • Yalcinkaya, Nazli (Department of Neuroscience, Institute for Experimental Medicine Research, Istanbul University) ;
  • Akan, Gokce (Molecular Endocrinology Laboratory, Department of Growth-Development and Pediatric Endocrinology, Child Health Institute, Istanbul University) ;
  • Arikan, Soykan (Department of General Surgery, Istanbul Training and Research Hospital) ;
  • Ozkok, Elif (Department of Neuroscience, Institute for Experimental Medicine Research, Istanbul University) ;
  • Cakmakoglu, Bedia (Department of Molecular Medicine, Institute for Experimental Medicine Research, Istanbul University) ;
  • Yaylim, Ilhan (Department of Molecular Medicine, Institute for Experimental Medicine Research, Istanbul University) ;
  • Aydin, Makbule (Department of Neuroscience, Institute for Experimental Medicine Research, Istanbul University) ;
  • Atalar, Fatmahan (Molecular Endocrinology Laboratory, Department of Growth-Development and Pediatric Endocrinology, Child Health Institute, Istanbul University)
  • Published : 2013.05.30


Background: Many breast cancers are caused by certain rare and familial mutations in the high or moderate penetrance genes BRCA1, BRCA2 and CHEK2. The aim of this study was to examine the allele and genotype frequencies of seven mutations in BRCA1, BRCA2 and CHEK2 genes in breast cancer patients and to investigate their isolated and combined associations with breast cancer risk. Methods: We genotyped seven mutations in BRCA1, BRCA2 and CHEK2 genes and then analyzed single variations and haplotype associations in 106 breast cancer patients and 80 healthy controls. Results: We found significant associations in the analyses of CHEK2- 1100delC (p=0.001) and BRCA1-5382insC (p=0.021) mutations in breast cancer patients compared to controls. The highest risk was observed among breast cancer patients carrying both CHEK2-1100delC and BRCA2- Met784Val mutations (OR=0.093; 95%CI 0.021-0.423; p=0.001). We identified one previously undescribed BRCA2 and a CHEK2 four-marker haplotype of A-C-G-C which was overrepresented ($X^2$=7.655; p=0.0057) in the patient group compared to controls. Conclusion: In this study, we identified a previously undescribed BRCA2 and CHEK2 A-C-G-C haplotype in association with the breast cancer in our population. Our results further suggest that the CHEK2-1100delC mutation in combination with BRCA2-Met784Val may lead to an unexpected high risk which needs to be confirmed in larger cohorts in order to better understand their role in the development and prognosis of breast cancer.


  1. Abeliovich D, Kaduri L, Lerer I, et al (1997). The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet, 60, 505-14.
  2. Adank MA, Jonker MA, Kluijt I, et al (2011). CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women. J Med Genet, 48, 860-3.
  3. Backe J, Hofferbert S, Skawran B, et al (1999). Frequency of BRCA1 mutation 5382insC in German breast cancer patients. Gynecol Oncol, 72, 402-6.
  4. Balci A, Huusko P, Pääkkonen K, et al (1999). Mutation analysis of BRCA1 and BRCA2 in Turkish cancer families: a novel mutation BRCA2 3414del4 found in male breast cancer. Eur J Cancer, 35, 707-10.
  5. Bartek J, Falck J, Lukas J (2001). Chk2 kinase [mdash] a busy messenger. Nature Reviews Molecular Cell Biology 2, 877-86.
  6. Berman DB, Costalas J, Schultz DC, et al (1996). A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals. Cancer Res, 56, 3409-14.
  7. CHEK2 Breast Cancer Case-Control Consortium (2004). 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, 1175-82.
  8. Cybulski C, Gorski B, Huzarski T, et al (2004). CHEK2 Is a Multiorgan Cancer Susceptibility Gene. Am J Hum Genet, 75, 131-5.
  9. Cybulski C, Gliniewicz B, Sikorski A, et al (2007). Epistatic relationship between the cancer susceptibility genes CHEK2 and p27. Cancer Epidemiol Biomarkers Prev, 16, 572-6.
  10. Desrichard A, Bidet Y, Uhrhammer N, Bignon YJ (2011). CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res, 13, 19.
  11. Diez O, Domenech M, Alonso MC, et al (1998). Identification of the 185delAG BRCA1 mutation in a Spanish Gypsy population. Hum Genet, 103, 707-8.
  12. Domagala P, Wokolorczyk D, Cybulski C, et al (2012). Different CHEK2 germline mutations are associated with distinct immunophenotypic molecular subtypes of breast cancer. Breast Cancer Res Treat, 132, 937-45.
  13. Dong X, Wang L, Taniguchi K, et al (2003). Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet, 72, 270-80.
  14. Einarsdottir K, Humphreys K, Bonnard C, et al (2006). Linkage Disequilibrium Mapping of CHEK2: Common Variation and Breast Cancer Risk. PLoS Med, 3, 168.
  15. Gabrovska PN, Smith RA, O'Leary G, et al (2011). Investigation of the 1758G>C and 2880A>G variants within the NCOA3 gene in a breast cancer affected Australian population. Gene 482, 68-72.
  16. Gorski B, Byrski T, Huzarski T, et al (2000). Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. Am J Hum Genet, 66, 963-8.
  17. Gudmundsdottir K, Ashworth A (2006). The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene, 25, 5864-74.
  18. Hansmann T, Pliushch G, Leubner M, et al (2012). Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer. Hum Mol Genet, 21, 4669-79.
  19. Health Statistics Yearbook (2010). The Ministry of Health of Turkey. Available at
  20. Iniesta MD, Gorin MA, Chien LC, et al (2010). Absence of CHEK2*1100delC mutation in families with hereditary breast cancer in North America. Cancer Genet Cytogenet , 202, 136-40.
  21. Ishitobi M, Miyoshi Y, Ando A, et al (2003). Association of BRCA2 polymorphism at codon 784 (Met/Val) with breast cancer risk and prognosis. Clin Cancer Res, 9, 1376-80.
  22. Konstantopoulou I, Kroupis C, Ladopoulou A, et al (2000). BRCA1 mutation analysis in breast/ovarian cancer families from Greece. Hum Mutat, 16, 272-3.<272::AID-HUMU17>3.0.CO;2-4
  23. Krupa R, Sliwinski T, Morawiec Z, et al (2009). Association between polymorphisms of the BRCA2 gene and clinical parameters in breast cancer. Exp Oncol, 31, 250-1.
  24. Levy-Lahad E, Catane R, Eisenberg S, et al (1997). Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Hum Genet, 60, 1059-67.
  25. Machackova E, Foretova L, Navratilova M, et al (2000). A high occurrence of BRCA1 and BRCA2 mutations among Czech hereditary breast and breast-ovarian cancer families. Cas Lek Cesk, 139, 635-7.
  26. Manguoglu AE, Luleci G, Ozçelik T, et al (2003). Germline mutations in the BRCA1 and BRCA2 genes in Turkish breast/ovarian cancer patients. Hum Mutat, 21, 444-5.
  27. Manguoğlu E, Guran S, Yamaç D, et al (2011). Genomic large rearrangement screening of BRCA1 and BRCA2 genes in high-risk Turkish breast/ovarian cancer patients by using multiplex ligation-dependent probe amplification assay. Cancer Invest, 29, 73-7.
  28. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al (2002). Low-penetrance susceptibility to breast cancer due to CHEK2-1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31, 55-9.
  29. 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.
  30. Ozdag H, Tez M, Sayek I, et al (2000). Germ line BRCA1 and BRCA2 gene mutations in Turkish breast cancer patients. Eur J Cancer, 36, 2076-82.
  31. Rohlfs EM, Learning WG, Friedman KJ, et al (1997). Direct detection of mutations in the breast and ovarian cancer susceptibility gene BRCA1 by PCR-mediated site-directed mutagenesis. Clin Chem, 43, 24-9.
  32. Saxena S, Chakraborty A, Kaushal M, et al (2006). Contribution of germline BRCA1 and BRCA2 sequence alterations to breast cancer in Northern India. BMC Med Genet, 4, 75.
  33. 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.
  34. Shuen AY, Foulkes WD (2011). Inherited mutations in breast cancer genes--risk and response. J Mammary Gland Biol Neoplasia, 16, 3-15.
  35. 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.
  36. Tereschenko IV, Basham VM, Ponder BA, Pharoah PD (2002). BRCA1 and BRCA2 mutations in Russian familial breast cancer. Hum Mutat, 19, 184.
  37. Vahteristo P, Bartkova J, Eerola H, et al (2002). A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet, 71, 432-8.
  38. Walsh T, Casadei S, Coats KH, et al (2006). Spectrum of Mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA, 295, 1379-88.
  39. Wasielewski M, Vasen H, Wijnen J, et al (2008). CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer. Clin Cancer Res, 14, 4989-94.
  40. Weischer M, Bojesen SE, Ellervik C, et al (2008). CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol, 26, 542-8.
  41. Wooster R, Bignell G, Lancaster J, et al (1995). Identification of the breast cancer susceptibility gene BRCA2. Nature, 378, 789-92.
  42. Yazici H, Bitisik O, Akisik E, et al (2000). BRCA1 and BRCA2 mutations in Turkish breast/ovarian families and young breast cancer patients. Br J Cancer, 83, 737-42.
  43. Yazici H, Glendon G, Yazici H, et al (2002). BRCA1 and BRCA2 mutations in Turkish familial and non-familial ovarian cancer patients: a high incidence of mutations in non-familial cases. Hum Mutat, 20, 28-34.
  44. Zhang S, Phelan CM, Zhang P, et al (2008). Frequency of the CHEK2 1100delC mutation among women with breast cancer: an international study. Cancer Res, 68, 2154-7.

Cited by

  1. Spectrum and frequencies of BRCA1/2 mutations in Bulgarian high risk breast cancer patients vol.15, pp.1, 2015,
  2. Absence of 185delAG and 6174delT Mutations among Breast Cancer Patients of Eastern India vol.16, pp.17, 2015,
  3. BRCA1 and BRCA2 Common Mutations in Iranian Breast Cancer Patients: a Meta Analysis vol.16, pp.3, 2015,
  4. Association of BRCA1, BRCA2, RAD51, and HER2 gene polymorphisms with the breast cancer risk in the Bangladeshi population vol.24, pp.2, 2017,
  5. Association Between CHEK2*1100delC and Breast Cancer: A Systematic Review and Meta-Analysis vol.22, pp.4, 2018,