Studying of the effect of the genetic variant c.470T>C in the CHEK2 gene on increasing the risk of breast cancer in the population of the Russian Federation

Introduction. Currently, there are conflicting data regarding the effect of the c.470T> C germline mutation in the CHEK2 gene on increasing the risk of breast cancer (BC), so it is necessary to conduct research on large samples of patients, including in the Russian population, in order to analyze the contribution of this mutation to the risk of cancer developing.

The aim of the study was to determine the frequency of occurrence of the genetic variant c.470Т>С in the CHEK2 gene in the Russian population in patients with BC and patients with benign breast diseases (BBD) to assess the possible effect of this deoxyribonucleic acid damage on the likelihood of cancer occurrence.

Materials and methods. The study included 2,787 patients with BC and 1,004 patients with BBD who underwent examination and treatment at the Russian Scientific Center of Roentgenoradiology of the Ministry of the Russian Federation from 2010 to 2018. Molecular genetic study was carried out by real-time polymerase chain reaction to determine the characteristic of the Russian population hereditary genetic variant c.470Т>С in the CHEK2 gene using a diagnostic panel that allows to determine three germline mutations: c.1100delC, c.444+1G>A and c.470Т>С in the CHEK2 gene.

Results. In patients with BC the frequency of the mutation c.470T>C in the CHEK2 gene was 3.8 %, in patients with BBD this mutation was detected in 4.7 % of cases. The frequency of the genetic variant c.470T>C in high-risk groups was: 5.1 % – for BC patients with clinical signs of hereditary disease and 4.9 % – for patients with BBD with a family history of cancer. There were no statistically significant differences between the frequency of the mutation c.470T>C in the general groups of BC patients and patients with BBD and the corresponding frequency in the high-risk groups, as well as in the groups of BC patients and patients with BBD (p >0.05).

Conclusion. The results of this study indicate the probable absence of a relationship between the presence of the mutation c.470Т>С in the CHEK2 gene and an increased risk of BC.

1. Stracker T.H., Usui T., Petrini J.H. Taking the time to make important decisions: the checkpoint effector kinases Chk1 and Chk2 and the DNA damage response. DNA Repair 2009;8(9):1047–54. DOI: 10.1016/j.dnarep.2009.04.012.

2. Bateneva E.I. A new diagnostic panel for detecting hereditary predisposition to breast cancer and ovarian cancer. Diss. … candidate of medical sciences. N.N. Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian. Moscow, 2015. 125 p. (In Russ.).

3. Weischer M., Bojesen S.E., Ellervik C. et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 2008;26(4): 542–8. DOI: 10.1200/JCO.2007.12.5922.

4. Bogdanova N., Enssen-Dubrowinskaja N., Feshchenko S. et al. Association of two mutations in the CHEK2 gene with breast cancer. Int J Cancer 2005;116:263–6. DOI: 10.1002/ijc.21022.

5. Cybulski C. Selected aspects of inherited susceptibility to prostate cancer and tumours of different site of origin. Hered Cancer Clin Pract 2007;5(3):164–79. DOI: 10.1186/1897-4287-5-3-164.

6. Kilpivaara O., Vahteristo P., Falck J. et al. CHEK2 variant I157T may be associated with increased breast cancer risk. Int J Cancer 2004;111:543–7. DOI: 10.1002/ijc.20299.

7. Liu C., Wang Y., Wang Q.S. et al. The CHEK2 I157T variant and breast cancer susceptibility: a systematic review and meta-analysis. Asian Pac J Cancer Prev 2012;13(4):1355–60. DOI: 10.7314/apjcp.2012.13.4.1355.

8. Han F.F., Guo C.L., Liu L.H. The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a metaanalysis. DNA Cell Biol 2013;32(6):329–35. DOI: 10.1089/dna.2013.1970.

9. Bermisheva M.A., Tahirova Z.R., Bogdanova N. et al. Frequency of CHEK2 gene mutations in patients with breast cancer from the republic of bashkortostan. Molekuljarnaja biologija = Molecular biology 2014;48(1):55–61. (In Russ.). DOI: 10.7868/S0026898414010029.

10. Schutte M., Seal S., Barfoot R. et al. Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Am J Hum Genet 2003;72(4):1023–8. DOI: 10.1086/373965.

11. Kleibl Z., Havranek O., Novotny J. et al. Analysis of CHEK2 FHA domain in Czech patients with sporadic breast cancer revealed distinct rare genetic alterations. Breast Cancer Res Treat 2008;112(1):159–64. DOI: 10.1007/s10549-007-9838-7.

12. Friedrichsen D.M., Malone K.E., Doody D.R. et al. Frequency of CHEK2 mutations in a population based, case– control study of breast cancer in young women. Breast Cancer Res 2004;6(6):629–35. DOI: 10.1186/bcr933.

13. Daly M.B., Pilarski R., Berry M. et al. NCCN Guidelines Insights: Genetic/ Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017. J Natl Compr Canc Netw 2017;15(1):9–20. DOI: 10.6004/jnccn.2017.0003.

14. Kaprin A.D., Kostin A.A., Zikyryahodzhayev A.D. et al. Breast cancer associated with carriage of a mutation СНЕК2. Akusherstvo i ginekologija = Obstetrics and gynecology 2018;(5):102–7. (In Russ.). DOI: 10.18565/aig.2018.5.102-7.

15. Paluch-Shimon S., Cardoso F., Sessa C. et al. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol 2016;27(5):103–10. DOI: 10.1093/annonc/mdw327.

16. Farahtdinova A., Fedorova S., Nikolaeva T. et al. Analiz mutacij v genah BRCA1, CHEK2, NBS1 u bol’nyh rakom molochnoj zhelezy iz Respubliki Saha(Yakutia). Jakutskij medicinskij zhurnal = Yakut Medical Journal 2009;2(26):91–3. (In Russ.).

17. Liu Y., Liao J., Xu Y. et al. A recurrent CHEK2 p.H371Y mutation is associated with breast cancer risk in chinese women. Hum Mutation 2011;32(9):1000–3. DOI: 10.1002/humu.21538.

18. Jalilvand M., Oloomi M., Najafipour R. et al. An association study between CHEK2 gene mutations and susceptibility to breast cancer. Comp Clin Pathol 2017;26(4): 837–45. DOI: 10.1007/s00580-017-2455-x.