Problems of Radiation Medicine and Radiobiology

L. A. Rybchenko, L. O. Poluben, G. M. Bychkova, G. V. Stephanovych, S. V. Klymenko

State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Yuriia Illienka St., Kyiv, 04050, Ukraine

MUTATIONS OF GENES BRCA1 AND BRCA2 IN WOMEN WITH OVARIAN CANCER EXPOSED TO FACTORS OF CHORNOBYL NUCLEAR ACCIDENT

Objective. to determine a frequency of germline mutations 185delAG, 5382insC in BRCA1 gene and 6174delT in BRCA2 gene in Ukrainian patients with OC including women who were exposed to the factors of Chornobyl nuclear accident. Material and methods. In the study we enrolled 306 OC patients of different age who were tested for the presence of the major BRCA1 and BRCA2 gene mutations using allele specific multiplex polymerase chain reaction. Results. The mutation frequency in patients exposed to IR with OC (main group) was 5.3 % (2 from 38). Among unexposed patients (control group) 11,2 % (30 from 268) of cases with mutation were identified. However, the difference between the groups was not significant (p = 0.39). It was shown that the BRCA1/2 mutations frequency in the patient of both groups was 10,4 % (32 from 306). The mutation BRCA1 5382insC was positive in 87.5 % (28 from 32) of cases, nevertheless nobody was identified with the allelic variant BRCA2 6174delT among both groups. There was a tendency toward an earlier age of the OC manifestation in the patients exposed to IR due to Chornobyl nuclear accident compared to BRCA-positive women of the control group (р = 0.06). When comparing BRCA-positive and BRCA-negative patients with OC of the main group, there was a statistical significance regarding the earlier age of the disease manifestation in the patients with mutations (р = 0.04). However, such difference was not observed in the control group (р = 0.22). Conclusions. The frequency of the mutations in exposed to IR and unexposed patients with OC does not differ and depends on a spectrum of studied BRCA1/2 gene mutations, level of DNA amplification and sample number. The allelic variant BRCA1 5382insC is dominant and accounts for 87.5 % of the total number of the found mutations. Due to the radiation factor the OC in the BRCA1-positive individuals is realized at the earlier age than in patients negative for these mutations. The incidence of OC after the Chornobyl accident was observed 27–38 years later in a cohort of women who were from 4 to 40 years old at the moment of the nuclear explosion.
Key words: ovarian cancer, BRCA1 and BRCA2 gene mutations, ionizing radiation, Chornobyl nuclear accident.

Problems of Radiation Medicine and Radiobiology.
2019;24:455-464. doi: 10.33145/2304-8336-2019-24-455-464

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1. Fedorenko ZP, Gulak LO, Mykhailovych YuI, Gorokh YeL, Ryzhov AYu, Sumkina OV, Kutsenko LB. [Cancer in Ukraine, 2016-2017: morbidity, mortality, performance indicators of cancer services] [Internet]. Bulletin of National Cancer Registry of Ukraine. 2018;(19). Available from: http://www.ncru.inf.ua/publications/BULL_19/index.htm. Ukrainian.

2. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68(3):700-10. DOI: 10.1086/318787.

3. Zhang S, Royer R, Li S, McLaughlin JR, Rosen B, Risch HA, et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011;121:353-7. DOI: https://doi.org/10.1016/j.ygyno.2011.01.020.

4. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al. Average risk of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117-30. DOI: https://doi.org/10.1086/375033.

5. Kobavashi H, Ohno S, Sasaki Y, Matsuura M. Hereditary breast and ovarian cancer susceptibility genes (review). Oncol Rep. 2013;30(3):1019-29. DOI: https://doi.org/10.3892/or.2013.2541.

6. Rybchenko L, Poluben L, Bychkova H, et al. Ovarian cancer and mutationfl status of BRCA1 and BRCA2 genes. Oncology (Ukraine). 2019;21(1):80.

7. Paliychuk OV, Polischuk LZ, Gorovenko NG, et al. [The role of genetic factors in the propensity to develop primary and multiple tumors of the organs of the female reproductive system]. Clinical Oncology. 2013;2(10):83-9. Ukrainian.

8. Bateneva EI, Filippova MG, Tylyantina AС, et al. [High frequency of mutations in the BRCA1, BRCA2, CHEK2, NBN, BLM genes in patients with ovarian cancer in the Russian population]. In: Tumors of the female reproductive system. 2014. Vol. 4. p. 51-6. Russian.

9. 9 Blecharz P, Szatkowski W, Klimek M, Urbanski K. [The prevalence of BRCA1 mutations among families at high-risk of breast and ovarian cancer in province of Malopolska between 2004-2009]. Przegl Lek. 2009;66(12):1046-8. Polish.

10. Elsakov P., Kurtinaitis J., Petraitis S, Ostapenko V, Razumas M, Razumas T, et al. The contribution of founder mutations in BRCA1 to breast and ovarian cancer in Lithuania. Clin Genet. 2010;78(4):373-6. DOI: https://doi.org/10.1111/j.1399-0004.2010.01404.x.

11. Rybchenko LA, Bychkova AM, Skyban GV, Yaroshenko NE, Klymenko SV. [The frequency analysis of the most common mutations in genes brca1 and brca2 in women, which took part in the liquidation of Chornobyl disaster consequences]. Probl Radiac Med Radiobiol. 2012;17:267-73. Ukrainian.

12. Baert A, Depuydt J, Maerkenet TV, Poppe B, Malfait F, Storm K, et al. Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation. Breast Cancer Res. 2016;18(1):52. DOI: 10.1186/s13058-016-0709-1.

13. Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA J. 2010;1(3):397-412. DOI: 10.1007/s13167-010-0037-y.

14. Pijpe A, Andrieu N, Easton DF, Kesminiene A, Cardis E, Nogues C, et al. Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK). BMJ. 2012;345:e5660. DOI: 10.1136/bmj.e5660.