Screening for mutations in BRCA1 and BRCA2 genes and related perspectives for the healthcare system

  • Y. O. Tabaliuk Bogomolet’s National Medical University, Ukraine, 01601, Kyiv boulevard Tarasa Shevchenko, 13
  • L. A. Rybchenko State Institution «National Research Center for Radiation Medicine of NAMS of Ukraine», Ukraine, 02000, Kyiv, Uriya Illenko str., 53
  • B. T. Klimuk State Institution «National Research Center for Radiation Medicine of NAMS of Ukraine», Ukraine, 02000, Kyiv, Uriya Illenko str., 53
  • S. V. Klymenko State Institution «National Research Center for Radiation Medicine of NAMS of Ukraine», Ukraine, 02000, Kyiv, Uriya Illenko str., 53


In the article there were looked some aspects of the knowledge regarding mutations in BRCA1 BRCA2 genes that have been accumulated since the first report on role of these genes in the development of breast and ovarian cancer. Most of them have practical worth related to the detection of mutations, as well as the prevention and treatment of associated ovarian cancer (the article focuses specifically on ovarian cancer, conditioned to relatively less amount of information on this pathology). There has been paid attention to the rational assignment of a genetic test on the presence of mutations in BRCA genes.
Keywords: ovarian cancer, mutations in BRCA1 BRCA2 genes, screening of the presence mutations in BRCA1 BRCA2 genes.


Antoniou A., Pharoah P. D. P., Narod S. et al. Average risks 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. American Journal of Human Genetic. 2003. Vol. 72, No. 5. P. 1117-1130. doi: 10.1086/375033.

Kwong A., Wong C. H. N., Suen D. T. K. et al. Accuracy of BRCA1/2 mutation prediction models for different ethnicities and genders: Experience in a Southern Chinese cohort. World Journal of Surgery. 2012. Vol. 36, No. 4. P. 702-713. doi: 10.1007/s00268-011-1406-y.

Audibert C., Perlaky A., Stuntz M, Glass D. Variability in the therapeutic management of advanced ovarian cancer patients: a five-country survey of oncologists. Drug Design Development and Therapy. 2017. Vol. 11. P. 3471-3479. doi: 10.2147/DDDT.S151420.

Baert A., Depuydt J., Van Maerken T. et al. Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation. Breast Cancer Res. 2016. Vol. 18. P. 52. doi: 10.1186/s13058-016-0709-1.

Bosetti C., Rosato V., Gallus S. et al. Aspirin and cancer risk: A quantitative review to. 2011. Ann. Oncol. 2012. Vol. 23, No.. 6. P. 1403-1415. doi: 10.1093/annonc/mds113.

Chen S., Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J. Clin. Oncol. 2007. Vol. 25, No. 11. P. 1329-1333. doi: 10.1200/JCO.2006.09.1066.

Coleman R. I., Oza A. M., Lorusso D. et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017. Vol. 390, No. 10106. P. 1949-1961. doi: 10.1016/S0140-6736(17)32440-6.

Beral V., Doll R., Hermon C. et al. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and oral contraceptives: Collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet. 2008. Vol. 371, No. 9609. P. 303-314. doi: 10.1016/S0140-6736(08)60167-1.

D’Amours D., Desnoyers S., D’Silva I., Poirier G. G. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem. J. 1999. Vol. 342 (Pt. 2). P. 249-268.

Demogines A., East A. M., Lee J. et al. Ancient and recent adaptive evolution of primate non-homologous end joining genes. PLoS Genet. 2010. Vol. 6, No. 10:e1001169. doi : 10.1371/journal.pgen.1001169.

Domchek S. M., Friebel T. M., Singer C. F. et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010. Vol. 304, No. 9. P. 967-975. doi: 10.1001/jama.2010.1237

Easton D. F., Bishop D. T., Ford D., Crockford G. P. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. American Journal of Human Genetic. 1993. Vol. 52, No. 4. P. 678-701.

Fedorenko Z. P., Hulak L. O., Mykhaylovych Y. Y. et al. Cancer in Ukraine, 2016-2017: morbidity, mortality, indicators of oncology service action. Bulletin of the National cancer register of Ukraine. 2018. No. 19 [in Ukrainian].

Finch A., Metcalfe K. A., Chiang J. K. et al. The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation. Gynecol. Oncol. 2011. Vol. 121, No. 1. P. 163-168. doi: 10.1016/j.ygyno.2010.12.326.

Finch A., Lubinski J., Mоller P. et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J. Clin. Oncol. 2014. Vol. 32. P. 1547-1553. doi: 10.1200/JCO.2013.53.2820.19.

Fisher L. D., Dixon D. O., Herson J. et al. Intention to treat in clinical trials. In: Peace KE, editor. Statistical issues in drug research and development. New York: Marcel Dekker. 1990. P. 331-350.

Gelmon K. A., Tischkowitz M., Mackay H. et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011. Vol. 12, No. 9. P. 852-861. doi: 10.1016/S1470-2045(11) 70214-5.

Gorodetska I., Serga S., Levkovich N. et al. The frequency of BRCA1 founder mutation c.5266dupC (5382insC) in breast cancer patients from Ukraine. Hereditary cancer in clinical practice. BioMedCentral. 2015. Vol. 13. P. 19. doi: 10.1186/s13053-015-0040-3.

Harmsen M. G., Inthout J., Arts-de Jong M. et al. Salpingectomy with delayed oophorectomy in BRCA1/2 mutation carriers: Estimating ovarian cancer risk. Obstet. Gynecol. 2016. Vol. 127, No. 6. P. 1054-1063. doi: 10.1097/A0G.0000000000001448.

Hassa P. O., Hottiger M. O. The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Front. Biosci. 2008. Vol. 13. P. 3046-3082. doi: 10.2741/2909

Heacock M. L., Stefanick D. F., Horton J. K., Wilson S. H. Alkylation DNA damage in combination with PARP inhibition results in formation of S-phase-dependent double-strand breaks. DNA Repair (Amst). 2010. Vol. 9. No. 8. P. 929-936. doi: 10.1016/j.dnarep.2010.05.007

Searching request on a clinical trials aggregation website for the key words: ovarian cancer + nivolumab. URL: (last accessed: 01.07.2019).

Searching request on a clinical trials aggregation website for the key words: ovarian cancer + parp. URL: (last accessed: 01.07.2019).

Searching request on a clinical trials aggregation website for the key words: fenretidine. URL: (last accessed: 01.07.2019).

Website of the National cancer institute of the USA. Column: dictionary; searching request: progression free survival. URL: (last accessed: 01.07.2019).

Official website of the screening program ROCA. URL: (last accessed: 01.07.2019).

Iodice S., Barile M, Rotmensz N. et al. Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: A meta-analysis. Eur. J. Cancer. 2010. Vol. 46, No. 12. P. 2275-2284. doi: 10.1016/j.ejca.2010.04.018.

Jacobs I. J., Menon U., Ryan A. et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A randomised controlled trial. Lancet. 2016. Vol. 387, No. 10022. P. 945-956. doi: 10.1016/S0140-6736(15)01224-6

Kitsera N. I., Shparyk Y. V., Bilynskyy B. T. et al. Analysis of mutations in BRCA1/2 gene in patient with family/hereditary breast cancer from Lviv region (Ukraine). Oncology. 2012. Vol. 14, No.1. P. 44-49 [in Ukrainian].

Liu J. F., Silver D. P. PARP Inhibitors: Science and Current Clinical Development. Current Opinion in Oncology. 2010. Vol. 22, No. 6. P. 567-572. doi: 10.1097/CCO.0b013e32833edbf8.

Li L., Mao X., Qin X. et al. Aspirin inhibits growth of ovarian cancer by upregulating caspase 3 and downregulating bcl-2. Oncol. Lett. 2016. Vol. 12, No. 1. P. 93-96. doi: 10.3892/ol.2016.4607.

Liu L., Hu Z., Zhang H. et al. Vitamin D postpones the progression of epithelial ovarian cancer induced by 7,12-dimethylbenz [a] anthracene both in vitro and in vivo. Onco Targets Ther. 2016. Vol. 9. P. 23652375. doi: 10.2147/OTT.S100581.

Mavaddat N., Peock S., Frost D. et al. EMBRACE. Cancer risks for BRCA1 and BRCA2 mutation carriers: Results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013. Vol. 105, Iss. 11. P. 812-822. doi: 10.1093/jnci/djt095.

Marchetti C., De Felice F., Palaia I. et al. Risk-reducing salpingo-oophorectomy: A meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA1 and BRCA2 mutation carriers. BMC Womens Health 2014. Vol. 14. P. 150. doi: 10.1186/s12905-014-0150-5.

Menkiszak J., Gronwald J., Gorski B. et al. Hereditary ovarian cancer in Poland. Int. J. Cancer. 2003. Vol. 106, Iss. 6. P. 942-945. doi: 10.1002/ijc.11338.

Morgan R. D., Clamp A. R., Evans D. G. et al. PARP inhibitors in platinum-sensitive high-grade serous ovarian cancer. Cancer Hemotherapy and Pharmacology. 2018. Vol. 81, No. 4, P.647-658. doi: 10.1007/s00280-018-3532-9

Moslehi R. Chu W., Karlan B., Fishman D., Risch H., Fields A., Smotkin D., Ben-David Y., Rosenblatt J., Russo D., Schwartz P., Tung N., Warner E., Rosen A., Friedman J., Brunet J. S., Narod S. A. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. American Journal of Human Genetics. 2000. Vol. 66, No. 4. P. 1259-1272. doi: 10.1086/302853

Oza A. M., Tinker A. V., Oaknin A. et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2. Gynecologic Oncology. 2017. Vol. 147, No. 2. P. 267-275. doi: 10.1016/j.ygyno.2017.08.022.

Penaloza-MacMaster P. CD8 T-cell regulation by T regulatory cells and the programmed cell death protein 1 pathway. Immunology. 2017. Vol. 151, Iss. 2, P. 146-153. doi: 10.1111/imm.12739

Pfeffer M. C., HO N. B., Singh T. K. The Evolution, Functions and Applications of the Breast Cancer Genes BRCA1 and BRCA2. Cancer Genomics Proteomics. 2017. Vol. 14, No. 5. P. 293-298. doi: 10.21873/cgp.20040.

Prakash R., Zhang Y., Feng W., Jasin M. Homologous recombination and human health: the roles of BRCA1, BRCA2 and associated proteins. Cold Spring Harb Perspect Biol. 2015. Vol. 7, No. 4. doi: 10.1101/cshperspect.a016600.

Rajan A., Kim C., Heery C. R. et al. Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: Role in advanced cancers. Hum. Vaccin. Immunother. 2016. Vol. 12, No. 9. P. 2219-2231. doi: 10.1080/21645515.2016.1175694.

Rebbeck T. R., Kauff N. D., Domcheck S. M. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J. Natl. Cancer. Inst. 2009. Vol. 101. P. 80-87. doi: 10.1093/jnci/djn442

Rocca W. A., Bower J. H., Maraganore D. M. et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007. Vol. 69, No. 11. P. 1074-1083. doi: 10.1212/01.wnl.0000276984.19542.e6.

Rocca W. A., Bower J. H., Maraganore D. M., Ahlskog J. E., Grossardt B. R., de Andrade M., Melton L. J. 3rd. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008. Vol. 70. No. 3. P. 200-209.

Rocca W. A., Gazzuola-Rocca L., Smith C. Y. et al. Accelerated accumulation of multimorbidity after bilateral oophorectomy: a population-based cohort study. Mayo Clin. Proc. 2016. Vol. 91, No. 11. P. 15771589. doi: 10.1016/j.mayocp.2016.08.002.

Roy R., Chun J., Powell S. N. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2016. Vol. 12 No. 1. P. 68-78. doi: 10.1038/nrc3181.

Rybchenko L. A., Bychkova H. M., Stefanovych H. V. et al. Algorithm for determination of genetic predisposition to development breast's cancer in women who have undergo ionic radiation exposure due to the accident on Chernobyl atomic power station (guidelines) [in Ukrainian], Kyiv, 2016, 27 p.

Sasieni P. D., Duffy S. W., Cuzick J. Ovarian cancer screening: UKCTOCS trial. Lancet. 2016. Vol. 387, Iss. 10038. P. 2602. doi: 10.1016/S0140-6736(16)30847-9.

Satoh M. S., Lindahl T. Role of poly(ADP-ribose) formation in DNA repair. Nature. 1992. Vol. 356. P. 356-358.

Seeliger K., Dukowic-Schulze S., Wurz-Wildersinn R., Pacher M, Puchta H. BRCA2 is a mediator of RAD51- and DMC1-facilitated homologous recombination in Arabidopsis thaliana. New Phytologist. 2012. Vol. 193, Iss. 2. P. 364-375. doi: 10.1111/j.1469-8137.2011.03947.x.

Sunada S., Nakanishi A., Miki Y. Crosstalk of DNA double-strand break repair pathways in poly(ADP-ribose) polymerase inhibitor treatment of breast cancer susceptibility gene 1/2-mutated cancer. Cancer Science. 2018. Vol. 109, No. 4. P. 893-899. doi: 10.1111/cas.13530.

Supino R., Crosti M., Clerici M. et al. Induction of apoptosis by fenretinide (4HPR) in human ovarian carcinoma cells and its association with retinoic acid receptor expression. Int. J. Cancer. 1996. Vol. 65, No. 4. P. 491-497. doi: 10.1002/(SICI)1097-0215(19960208)65:4<491::AID-IJC17>3.0.CO;2-D.

Suspitsin E. N., Sherina N. Y., Ponomariova D. N. et al. High frequency of BRCA1, but not CHEK2 or NBS1 (NBN), founder mutations in Russian ovarian cancer patients. Hereditary Cancer in Clinical Practice. BioMedCentral. 2009. Vol. 7, No. 1. P. 5. doi: 10.1186/18974287-7-5.

Tschernichovsky R., Goodman A. Risk-reducing strategies for ovarian cancer in BRCA mutation carriers: a balancing act. The Oncologist. 2017. Vol. 22 No. 4. P. 450-459. doi: 10.1634/theoncologist.2016-0444.

Trapp O., Seeliger K., Puchta H. Homologs of breast cancer genes in plants. Front Plant Sci. 2011. Vol. 2, No. 19. P. 1-17. doi: 10.3389/fpls.2011.00019.

Tsoref D., Panzarella T., Oza A. Aspirin in prevention of ovarian cancer: Are we at the tipping point? Journal of the National Cancer Institute. 2014. Vol. 106, No. 2. doi: 10.1093/jnci/djt453.

Yin L., Grandi N., Raum E. et al. Meta-analysis: Circulating vitamin D and ovarian cancer risk. Gynecol Oncol. 2011. Vol. 121, No. 2. P. 369-375. doi: 10.1016/j.ygyno.2011.01.023.