Frequency and spectrum of founder and non-founder BRCA1 and BRCA2 mutations in a large series of Russian breast cancer and ovarian cancer patients

Abstract

Background

The spectrum of BRCA1 and BRCA2 mutations in Slavic countries is characterized by a high prevalence of founder alleles.

Methods

We analyzed a large data set of Russian breast cancer (BC) and ovarian cancer (OC) patients, who were subjected to founder mutation tests or full-length BRCA1 and BRCA2 analysis.

Results

The most commonly applied test, which included four founder mutations (BRCA1: 5382insC, 4153delA, 185delAG; BRCA2: 6174delT), identified BRCA1 or BRCA2 heterozygosity in 399/8533 (4.7%) consecutive BC patients, 230/2317 (9.9%) OC patients, and 30/118 (25.4%) women with a combination of BC and OC. The addition of another four recurrent BRCA1 mutations to the test (BRCA1 C61G, 2080delA, 3819del5, 3875del4) resulted in evident increase in the number of identified mutation carriers (BC: 16/993 (1.6%); OC: 34/1289 (2.6%); BC + OC: 2/39 (5.1%)). Full-length sequencing of the entire BRCA1 and BRCA2 coding region was applied to 785 women, very most of whom demonstrated clinical signs of BRCA-driven disease, but turned out negative for all described above founder alleles. This analysis revealed additional BRCA1 or BRCA2 mutation carriers in 54/282 (19.1%) BC, 50/472 (10.6%) OC, and 13/31 (42%) BC + OC patients. The analysis of frequencies of founder and “rare” BRCA1 and BRCA2 pathogenic alleles across various clinical subgroups (BC vs. OC vs. BC + OC; family history positive vs. negative; young vs. late-onset; none vs. single vs. multiple clinical indicators of BRCA1- or BRCA2-associated disease) revealed that comprehensive BRCA1 and BRCA2 analysis increased more than twice the number of identified mutation carriers in all categories of the examined women.

Conclusion

Full-length BRCA1 and BRCA2 sequencing is strongly advised to Slavic subjects, who have medical indications for BRCA1 and BRCA2 testing but are negative for recurrent BRCA1 and BRCA2 mutations.

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Abbreviations

BC:

Breast cancer

NGS:

Next-generation sequencing

OC:

Ovarian cancer

PCR:

Polymerase chain reaction

References

  1. 1.

    Kast K, Rhiem K, Wappenschmidt B, Hahnen E, Hauke J, Bluemcke B, Zarghooni V, Herold N, Ditsch N, Kiechle M, Braun M, Fischer C, Dikow N, Schott S, Rahner N, Niederacher D, Fehm T, Gehrig A, Mueller-Reible C, Arnold N, Maass N, Borck G, de Gregorio N, Scholz C, Auber B, Varon-Manteeva R, Speiser D, Horvath J, Lichey N, Wimberger P, Stark S, Faust U, Weber BH, Emons G, Zachariae S, Meindl A, Schmutzler RK, Engel C, German Consortium for Hereditary Breast, and Ovarian Cancer (GCHBOC) (2016) Prevalence of BRCA1/2 germline mutations in 21401 families with breast and ovarian cancer. J Med Genet 53:465–471. https://doi.org/10.1136/jmedgenet-2015-103672

    CAS  Article  Google Scholar 

  2. 2.

    Neff RT, Senter L, Salani R (2017) BRCA mutation in ovarian cancer: testing, implications and treatment considerations. Ther Adv Med Oncol 9:519–531. https://doi.org/10.1177/1758834017714993

    CAS  Article  Google Scholar 

  3. 3.

    Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, Garber JE, Neuhausen SL, Matloff E, Eeles R, Pichert G, Van t'veer L, Tung N, Weitzel JN, Couch FJ, Rubinstein WS, Ganz PA, Daly MB, Olopade OI, Tomlinson G, Schildkraut J, Blum JL, Rebbeck TR (2010) Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 304:967–975. https://doi.org/10.1001/jama.2010.1237

    CAS  Article  Google Scholar 

  4. 4.

    Ludwig KK, Neuner J, Butler A, Geurts JL, Kong AL (2016) Risk reduction and survival benefit of prophylactic surgery in BRCA mutation carriers, a systematic review. Am J Surg 212:660–669. https://doi.org/10.1016/j.amjsurg.2016.06.010

    Article  Google Scholar 

  5. 5.

    Paluch-Shimon S, Cardoso F, Sessa C, Balmana J, Cardoso MJ, Gilbert F, Senkus E, Guidelines Committee ESMO (2016) 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 27(suppl 5):v103–v110. https://doi.org/10.1093/annonc/mdw327

    CAS  Article  Google Scholar 

  6. 6.

    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917. https://doi.org/10.1038/nature03443

    CAS  Article  Google Scholar 

  7. 7.

    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921. https://doi.org/10.1038/nature03445

    CAS  Article  Google Scholar 

  8. 8.

    Byrski T, Huzarski T, Dent R, Marczyk E, Jasiowka M, Gronwald J, Jakubowicz J, Cybulski C, Wisniowski R, Godlewski D, Lubinski J, Narod SA (2014) Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 147:401–405. https://doi.org/10.1007/s10549-014-3100-x

    CAS  Article  Google Scholar 

  9. 9.

    Iyevleva AG, Imyanitov EN (2016) Cytotoxic and targeted therapy for hereditary cancers. Hered Cancer Clin Pract 14(1):17. https://doi.org/10.1186/s13053-016-0057-2

    CAS  Article  Google Scholar 

  10. 10.

    Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA (1999) The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 64:963–970. https://doi.org/10.1086/302320

    CAS  Article  Google Scholar 

  11. 11.

    Tulinius H, Olafsdottir GH, Sigvaldason H, Arason A, Barkardottir RB, Egilsson V, Ogmundsdottir HM, Tryggvadottir L, Gudlaugsdottir S, Eyfjord JE (2002) The effect of a single BRCA2 mutation on cancer in Iceland. J Med Genet 39:457–462. https://doi.org/10.1136/jmg.39.7.457

    CAS  Article  Google Scholar 

  12. 12.

    Górski B, Jakubowska A, Huzarski T, Byrski T, Gronwald J, Grzybowska E, Mackiewicz A, Stawicka M, Bebenek M, Sorokin D, Fiszer-Maliszewska Ł, Haus O, Janiszewska H, Niepsuj S, Góźdź S, Zaremba L, Posmyk M, Płuzańska M, Kilar E, Czudowska D, Waśko B, Miturski R, Kowalczyk JR, Urbański K, Szwiec M, Koc J, Debniak B, Rozmiarek A, Debniak T, Cybulski C, Kowalska E, Tołoczko-Grabarek A, Zajaczek S, Menkiszak J, Medrek K, Masojć B, Mierzejewski M, Narod SA, Lubiński J (2004) A high proportion of founder BRCA1 mutations in Polish breast cancer families. Int J Cancer 110:683–686. https://doi.org/10.1002/ijc.20162

    CAS  Article  Google Scholar 

  13. 13.

    Savanevich A, Oszurek O, Lubiński J, Cybulski C, Dębniak T, Narod SA, Gronwald J (2014) BRCA1 founder mutations compared to ovarian cancer in Belarus. Fam Cancer 13:445–447. https://doi.org/10.1007/s10689-014-9721-8

    CAS  Article  Google Scholar 

  14. 14.

    Sokolenko AP, Mitiushkina NV, Buslov KG, Bit-Sava EM, Iyevleva AG, Chekmariova EV, Kuligina ESh, Ulibina YM, Rozanov ME, Suspitsin EN, Matsko DE, Chagunava OL, Trofimov DY, Devilee P, Cornelisse C, Togo AV, Semiglazov VF, Imyanitov EN (2006) High frequency of BRCA1 5382insC mutation in Russian breast cancer patients. Eur J Cancer 42:1380–1384. https://doi.org/10.1016/j.ejca.2006.01.050

    CAS  Article  Google Scholar 

  15. 15.

    Sokolenko AP, Rozanov ME, Mitiushkina NV, Sherina NY, Iyevleva AG, Chekmariova EV, Buslov KG, Shilov ES, Togo AV, Bit-Sava EM, Voskresenskiy DA, Chagunava OL, Devilee P, Cornelisse C, Semiglazov VF, Imyanitov EN (2007) Founder mutations in early-onset, familial and bilateral breast cancer patients from Russia. Fam Cancer 6:281–286. https://doi.org/10.1007/s10689-007-9120-5

    CAS  Article  Google Scholar 

  16. 16.

    Iyevleva AG, Suspitsin EN, Kroeze K, Gorodnova TV, Sokolenko AP, Buslov KG, Voskresenskiy DA, Togo AV, Kovalenko SP, Nv S, Devilee P, Imyanitov EN (2010) Non-founder BRCA1 mutations in Russian breast cancer patients. Cancer Lett 298:258–263. https://doi.org/10.1016/j.canlet.2010.07.013

    CAS  Article  Google Scholar 

  17. 17.

    Golden Helix GenomeBrowse ® visualization tool (Version 2.x) [Software]. Bozeman, MT: Golden Helix, Inc. https://www.goldenhelix.com.

  18. 18.

    Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, McGuffog L, Mazoyer S, Chenevix-Trench G, Easton DF, Antoniou AC, Nathanson KL, and the CIMBA Consortium (2015) Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313:1347–1361. https://doi.org/10.1001/jama.2014.5985

    CAS  Article  Google Scholar 

  19. 19.

    Manahan ER, Kuerer HM, Sebastian M, Hughes KS, Boughey JC, Euhus DM, Boolbol SK, Taylor WA (2019) Consensus Guidelines on Genetic` Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons. Ann Surg Oncol 26:3025–3031. https://doi.org/10.1245/s10434-019-07549-8

    Article  Google Scholar 

  20. 20.

    Kluska A, Balabas A, Paziewska A, Kulecka M, Nowakowska D, Mikula M, Ostrowski J (2015) New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing. BMC Med Genomics 8:19. https://doi.org/10.1186/s12920-015-0092-2

    CAS  Article  Google Scholar 

  21. 21.

    Brozek I, Cybulska C, Ratajska M, Piatkowska M, Kluska A, Balabas A, Dabrowska M, Nowakowska D, Niwinska A, Pamula-Pilat J, Tecza K, Pekala W, Rembowska J, Nowicka K, Mosor M, Januszkiewicz-Lewandowska D, Rachtan J, Grzybowska E, Nowak J, Steffen J, Limon J (2011) Prevalence of the most frequent BRCA1 mutations in Polish population. J Appl Genet 52:325–330. https://doi.org/10.1007/s13353-011-0040-6

    Article  Google Scholar 

  22. 22.

    Kowalik A, Siołek M, Kopczyński J, Krawiec K, Kalisz J, Zięba S, Kozak-Klonowska B, Wypiórkiewicz E, Furmańczyk J, Nowak-Ozimek E, Chłopek M, Macek P, Smok-Kalwat J, Góźdź S (2018) BRCA1 founder mutations and beyond in the Polish population: A single-institution BRCA1/2 next-generation sequencing study. PLoS ONE 13:e0201086. https://doi.org/10.1371/journal.pone.0201086

    CAS  Article  Google Scholar 

  23. 23.

    Cybulski C, Kluźniak W, Huzarski T, Wokołorczyk D, Kashyap A, Rusak B, Stempa K, Gronwald J, Szymiczek A, Bagherzadeh M, Jakubowska A, Dębniak T, Lener M, Rudnicka H, Szwiec M, Jarkiewicz-Tretyn J, Stawicka M, Domagała P, Narod SA, Lubiński J, Akbari MR, Polish Hereditary Breast Cancer Consortium (2019) The spectrum of mutations predisposing to familial breast cancer in Poland. Int J Cancer 145:3311–3320. https://doi.org/10.1002/ijc.32492

    CAS  Article  Google Scholar 

  24. 24.

    Gorodnova T, Sokolenko A, Ni V, Ivantsov A, Kotiv K, Petrik S, Amelina I, Berlev I, Imyanitov E (2019) BRCA1-associated and sporadic ovarian carcinomas: outcomes of primary cytoreductive surgery or neoadjuvant chemotherapy. Int J Gynecol Cancer 29:779–786. https://doi.org/10.1136/ijgc-2018-000175

    Article  Google Scholar 

  25. 25.

    Gorodnova TV, Kotiv KB, Ivantsov AO, Mikheyeva ON, Mikhailiuk GI, Lisyanskaya AS, Mikaya NA, Guseynov KD, Bondarev NE, Matveyeva NS, Nekrasova EA, Sidoruk AA, Roman LD, Manikhas GM, Belyaev AM, Sokolenko AP, Berlev IV, Imyanitov EN (2018) Efficacy of Neoadjuvant Therapy With Cisplatin Plus Mitomycin C in BRCA1-Mutated Ovarian Cancer. Int J Gynecol Cancer 28:1498–1506. https://doi.org/10.1097/IGC.0000000000001352

    Article  Google Scholar 

  26. 26.

    Preobrazhenskaya EV, Bizin IV, Kuligina ES, Shleykina AY, Suspitsin EN, Zaytseva OA, Anisimova EI, Laptiev SA, Gorodnova TV, Belyaev AM, Imyanitov EN, Sokolenko AP (2017) Detection of BRCA1 gross rearrangements by droplet digital PCR. Breast Cancer Res Treat 165:765–770. https://doi.org/10.1007/s10549-017-4357-7

    CAS  Article  Google Scholar 

  27. 27.

    Mancini-DiNardo D, Judkins T, Kidd J, Bernhisel R, Daniels C, Brown K, Meek K, Craft J, Holladay J, Morris B, Roa BB (2019) Detection of large rearrangements in a hereditary pan-cancer panel using next-generation sequencing. BMC Med Genomics 12(1):138. https://doi.org/10.1186/s12920-019-0587-3

    CAS  Article  Google Scholar 

  28. 28.

    Moiseyenko VM, Chubenko VA, Moiseyenko FV, Zagorskaya LA, Zaytseva YA, Gesha NE, Zykov EN, Ni VI, Preobrazhenskaya EV, Sokolenko AP, Imyanitov EN (2018) “Lazarus Response” to Olaparib in a Virtually Chemonaive Breast Cancer Patient Carrying Gross BRCA2 Gene Deletion. Cureus 10(2):e2150. https://doi.org/10.7759/cureus.2150

    Article  Google Scholar 

  29. 29.

    Sokolenko AP, Imyanitov EN (2018) Molecular Diagnostics in Clinical Oncology. Front Mol Biosci 5:76. https://doi.org/10.3389/fmolb.2018.00076

    CAS  Article  Google Scholar 

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Acknowledgements

We cordially thank patients and physicians, who participated in this study. We also thank the Russian Society for Clinical Oncology for the support of this investigation.

Funding

The study was supported by the Russian Foundation for Basic Research [Grant Nos. 20‐515-00002 and 19‐515-25001]. The analysis of breast cancer patients was partially supported by the research Grant #56223641 from Pfizer. A part of gene sequencing was supported by the Grant 075‐15-2019‐1669 from the Ministry of Science and Higher Education of the Russian Federation. The funding sources had no role in the study design, in the preparation of the manuscript or in the decision to submit the manuscript for publication.

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Correspondence to Anna P. Sokolenko.

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The study design was approved by the local Ethical Committee. All procedures performed in study were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Sokolenko, A.P., Sokolova, T.N., Ni, V.I. et al. Frequency and spectrum of founder and non-founder BRCA1 and BRCA2 mutations in a large series of Russian breast cancer and ovarian cancer patients. Breast Cancer Res Treat 184, 229–235 (2020). https://doi.org/10.1007/s10549-020-05827-8

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Keywords

  • BRCA1 and BRCA2 testing
  • Founder mutation
  • Hereditary breast cancer
  • Next-generation sequencing
  • Ovarian cancer