Spectrum of pathogenic variants associated with hereditary breast and ovarian cancer in the Republic of Dagestan

Background. A significant proportion of patients with breast cancer (BC) and ovarian cancer (OC) are carriers of pathogenic variants in the genes of hereditary cancer syndromes. Most often, hereditary forms of BC and OC are associated with alterations in the BRCA1 and BRCA2 genes. At the same time, the spectrum of mutations varies among representatives of different ethnic groups, reflecting the features of the genetic load. The population of Dagestan has unique genetic landscape due to historical and demographic factors. The republic is one of the most multinational regions of the Russian Federation, where representatives of numerous ethnolinguistic groups live (Avars, Lezgins, Dargins, Laks, etc.), which suggests the existence of recurring pathogenic genetic variants, i.e., the presence of a “founder effect” among representatives of the Dagestan peoples.

The aim of this work was an in-depth study of hereditary breast and ovarian cancer in the Republic of Dagestan.

Material and Methods. The study included 610 patients representing various nationalities of the Republic of Dagestan. The coding sequences of BRCA1, BRCA2, PALB2, ATM, TP53, CHEK2, NBN, BRIP1, BARD1, RAD51, RAD51B, RAD51C, RAD51D, and RAD54L were analyzed using targeted high-throughput sequencing.

Results. The most frequent pathogenic variants in the study group were BRCA1 c.66dup, c.115T>C [p.Cys39Arg], c.4709del and BRCA2 p.Gln3299Ter and c.5621_5624del. Among other genes, only CHEK2 c.817_818del pathogenic allele was recurrent. Several ethnospecific variants of the BRCA1 and BRCA2 genes were identified, which were dominant in certain ethnic groups in the Republic of Dagestan. In patients of Lezgin origin, the BRCA1 c.66dup allele was predominant (7/12 (58 %) of all BRCA1/2 variants in this ethnic group), and in Dargins, BRCA1 c.4709del (4/12 (33 %)). Several recurrent variants were identified in Avars, all of which in the BRCA2 gene: p.Gln3299Ter (8/21 (38 %) of all BRCA1/2 variants in Avars), c.5621_5624del (5/21 (24 %)), p.Arg2659Lys (3/21 (14 %)). A founder effect was also observed in the Laks: all cases of BRCA1/2 mutations were represented by a single BRCA2 allele (c. 429del). The BRCA1 p.Cys39Arg variant was found in several ethnic groups: Kumyks, Avars, and Dargins. In patients of Tabasaran origin, pathogenic variants were not identified.

Conclusion. The diversity of the identified mutations reflects the long-term migration processes and ethnic uniqueness of the Dagestan population.

1. Daly M.B., Pal T., Maxwell K.N., Churpek J., Kohlmann W., Al Hilli Z., Arun B., Buys S.S., Cheng H., Domchek S.M., Friedman S., Giri V., Goggins M., Hagemann A., Hendrix A., Hutton M.L., Karlan B.Y., Kassem N., Khan S., Khoury K., Kurian A.W., Laronga C., Mak J.S., Mansour J., McDonnell K., Menendez C.S., Merajver S.D., Norquist B.S., Offit K., Rash D., Reiser G., Senter-Jamieson L., Shannon K.M., Visvanathan K., Welborn J., Wick M.J., Wood M., Yurgelun M.B., Dwyer M.A., Darlow S.D. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024. J Natl Compr Canc Netw. 2023; 21(10): 1000–1010. doi: 10.6004/jnccn.2023.0051.

2. Arnon J., Zick A., Maoz M., Salaymeh N., Gugenheim A., Marouani M., Mor E., Hamburger T., Saadi N., Elia A., Ganz G., Fahham D., Meirovitz A., Kadouri L., Meiner V., Yablonski-Peretz T., Shkedi-Rafid S. Clinical and genetic characteristics of carriers of the TP53 c.541C>T, p.Arg181Cys pathogenic variant causing hereditary cancer in patients of Arab-Muslim descent. Fam Cancer. 2024; 23(4): 531–42. doi: 10.1007/s10689-024-00391-2.

3. El Biad O., Laraqui A., El Boukhrissi F., Mounjid C., Lamsisi M., Bajjou T., Elannaz H., Lahlou A.I., Kouach J., Benchekroune K., Oukabli M., Chahdi H., Ennaji M.M., Tanz R., Sbitti Y., Ichou M., Ennibi K., Badaoui B., Sekhsokh Y. Prevalence of specific and recurrent/founder pathogenic variants in BRCA genes in breast and ovarian cancer in North Africa. BMC Cancer. 2022; 22(1): 208. doi: 10.1186/s12885-022-09181-4.

4. Kechin A., Boyarskikh U., Barinov A., Tanas A., Kazakova S., Zhevlova A., Khrapov E., Subbotin S., Mishukova O., Kekeeva T., Demidova I., Filipenko M. A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia. Breast Cancer Res Treat. 2023; 197(2): 387–95. doi: 10.1007/s10549-022-06782-2.

5. Yanus G.A., Savonevich E.L., Sokolenko A.P., Romanko A.A., Ni V.I., Bakaeva E.K., Gorustovich O.A., Bizin I.V., Imyanitov E.N. Founder vs. non-founder BRCA1/2 pathogenic alleles: the analysis of Belarusian breast and ovarian cancer patients and review of other studies on ethnically homogenous populations. Fam Cancer. 2023; 22(1): 19–30. doi: 10.1007/s10689-022-00296-y.

6. Sokolenko A.P., Bakaeva E.K., Venina A.R., Kuligina E.S., Romanko A.A., Aleksakhina S.N., Belysheva Y.V., Belogubova E.V., Stepanov I.A., Zaitseva O.A., Yatsuk O.S., Togo A.V., Khamgokov Z.M., Kadyrova A.O., Pirmagomedov A.S., Bolieva M.B., Epkhiev A.A., Tsutsaev A.K., Chakhieva M.D., Khabrieva K.M., Khabriev I.M., Murachuev M.A., Buttaeva B.N., Baboshkina L.S., Bayramkulova F.I., Katchiev I.R., Alieva L.K., Raskin G.A., Orlov S.V., Khachmamuk Z.K., Levonyan K.R., Gichko D.M., Kirtbaya D.V., Degtyariov A.M., Sultanova L.V., Musayeva H.S., Belyaev A.M., Imyanitov E.N. Ethnicity-specific BRCA1, BRCA2, PALB2, and ATM pathogenic alleles in breast and ovarian cancer patients from the North Caucasus. Breast Cancer Res Treat. 2024; 203(2): 307–15. doi: 10.1007/s10549-023-07135-3.

7. Results of the 2020 All-Russian Population Census. Volume 5. Ethnic Composition and Language Proficiency. 5.1. Ethnic Composition of the Population of the Republic of Dagestan (in Russian)]. [Internet]. [cited 30.05.2025]. URL: https://05.rosstat.gov.ru/itogi.

8. Абдусаламов М.П.Б. История Дагестана. Курс лекций. Учебное пособие для студентов. Махачкала, 2016. 73 с. [Abdusalamov M.P.B. History of Dagestan. Makhachkala, 2016. 73 p. (in Russian)].

9. Aglarov M.A. Ethnogenesis in the light of political anthropology and ethnonymy in Dagestan. Makhachkala, 2013. 143 p. (in Russian).

10. Bardakov S.N., Deev R.V., Magomedova R.M., Umakhanova Z.R., Allamand V., Gartioux C., Zulfugarov K.Z., Akhmedova P.G., Tsargush V.A., Titova A.A., Mavlikeev M.O., Zorin V.L., Chernets E.N., Dalgatov G.D., Konovalov F.A., Isaev A.A. Intrafamilial Phenotypic Variability of Collagen VI-Related Myopathy Due to a New Mutation in the COL6A1 Gene. J Neuromuscul Dis. 2021; 8(2): 273–85. doi: 10.3233/JND-200476.

11. Semenova N.A., Kurkina M.V., Marakhonov A.V., Dadali E.L., Taran N.N., Strokova T.V. A novel mutation in the PEX26 gene in a family from Dagestan with members affected by Zellweger spectrum disorder. Mol Genet Metab Rep. 2021; 27: 100754. doi: 10.1016/j.ymgmr.2021.100754.

12. Rudenskaya G.E., Bostanova F.M., Medvedeva A.S., Lotnik E.E., Chausova P.A., Shchagina O.A. A case of rare hereditary Siddiqi syndrome with novel neuropsychiatric signs. S.S. Korsakov Journal of Neurology and Psychiatry. 2024; 124(12): 171–76. (in Russian). doi: 10.17116/jnevro2024124121171. EDN: DRLNIJ.

13. Bardakov S.N., Deev R.V., Isaev А.А., Khromov-Borisov N.N., Kopylov E.D., Savchuk М.R., Pushkin M.S., Presnyakov E.V., Magomedova R.M., Achmedova P.G., Umakhanova Z.R., Kaimonov V.S., Musatova E.V., Blagodatskikh K.А., Tveleneva A.А., Sofronova Y.V., Yakovlev I.A. Genetic screening of an endemic mutation in the DYSF gene in an isolated, mountainous population in the Republic of Dagestan. Mol Genet Genomic Med. 2023; 11(10): 2236. doi: 10.1002/mgg3.2236.

14. Voskoboeva E., Semyachkina A., Miklyaev O., Gamzatova A., Mikhaylova S., Vashakmadze N., Baydakova G., Omzar O., Pichkur N., Zakharova E., Kutsev S. Epidemiology and Genetics of Mucopolysaccharidosis Type VI in Russia. Front Mol Biosci. 2022; 8: 780184. doi: 10.3389/fmolb.2021.780184.

15. Bozhkova V.P., Khashaev ZKh., Umanskaia T.M. Frequency and the mutation spectrum of GJB2-related disorders of hearing in children from Dagestan as compared with the central European part of Russia. Biophysics. 2010; 55(3): 514–25. (in Russian). EDN: MVKFGP.

16. Rebbeck T.R., Friebel T.M., Friedman E., et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018; 39(5): 593–620. doi: 10.1002/humu.23406.

17. Khamgokov Z.M., Zagrebin F.A., Yanus G.A., Venina A.R., Romanko A.A., Pirmagomedov A.Sh., Kadyrova A.O., Belogubova E.V., Dzheus E.I., Sokolenko A.P., Imyanitov E.N. Spectrum of BRCA1, BRCA2, PALB2, ATM and TP53 mutations in breast and ovarian cancer patients from Kabardino-Balkaria. Problems in Oncology. 2024; 70(6): 1150–56. (in Russian). doi: 10.37469/0507-3758-2024-70-6-1150-1156. EDN: JVWEGD.

18. Preobrazhenskaya E.V., Shleykina A.U., Gorustovich O.A., Martianov A.S., Bizin I.V., Anisimova E.I., Sokolova T.N., Chuinyshena S.A., Kuligina E.S., Togo A.V., Belyaev A.M., Ivantsov A.O., Sokolenko A.P., Imyanitov E.N. Frequency and molecular characteristics of PALB2associated cancers in Russian patients. Int J Cancer. 2021; 148(1): 203–10. doi: 10.1002/ijc.33317.

19. Solsky I., Chen J., Rebbeck T.R. Precision prophylaxis: Identifying the optimal timing for risk-reducing salpingo-oophorectomy based on type of BRCA1 and BRCA2 cluster region mutations. Gynecol Oncol. 2020; 156(2): 363–76. doi: 10.1016/j.ygyno.2019.11.036.

20. Akamandisa M.P., Boddicker N.J., Yadav S., Hu C., Hart S.N., Ambrosone C.B., Anton-Culver H., Auer P.L., Bodelon C., Burnside E.S., Chen F., Eliassen A.H., Goldgar D.E., Haiman C., Hodge J.M., Huang H., John E.M., Karam R., Lacey J.V., Lindstroem S., Martinez M.E., Na J., Neuhausen S.L., O’Brien K.M., Olson J.E., Pal T., Palmer J.R., Patel A.V., Pesaran T., Polley E.C., Richardson M.E., Ruddy K.J., Sandler D.P., Teras L.R., Trentham-Dietz A., Vachon C.M., Weinberg C., Winham S.J., Yao S., Zirpoli G., Kraft P., Weitzel J.N., Domchek S.M., Couch F.J., Nathanson K.L. Association of gene variant type and location with breast cancer risk in the general population. Ann Oncol. 2025; 36(8): 954–63. doi: 10.1016/j.annonc.2025.04.010.

21. Schwartz C.J., Khorsandi N., Blanco A., Mukhtar R.A., Chen Y.Y., Krings G. Clinicopathologic and genetic analysis of invasive breast carcinomas in women with germline CHEK2 variants. Breast Cancer Res Treat. 2024; 204(1): 171–79. doi: 10.1007/s10549-023-07176-8.

22. Toss A., Tenedini E., Piombino C., Venturelli M., Marchi I., Gasparini E., Barbieri E., Razzaboni E., Domati F., Caggia F., Grandi G., Combi F., Tazzioli G., Dominici M., Tagliafico E., Cortesi L. Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers. Genes (Basel). 2021; 12(5): 616. doi: 10.3390/genes12050616.

23. Dejaegher K., Nevelsteen I., Han S., Verhoeven J., Wildiers H., Punie K. Hereditary breast cancer beyond BRCA: clinicopathological characteristics and long-term outcomes. Fam Cancer. 2025; 24(2): 54. doi: 10.1007/s10689-025-00478-4.

24. Kuchenbaecker K.B., Hopper J.L., Barnes D.R., et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017; 317(23): 2402–16. doi: 10.1001/jama.2017.7112.