Genetic features of breast cancer patients and women with a cancer-prone family history

Introduction. 5–10% of breast cancer (BC) cases are associated with germline pathogenic variants (PVs) in predisposition genes. In Russia, detection of “8 frequent” BRCA1,2 variants by PCR is recommended, with next generation sequensing (NGS) performed only at a second stage. Most studies on BC PVs have focused on BRCA1,2, not exploring other candidate genes.

Aim. Analyze the frequency and spectrum of PVs in candidate genes in patients with BC and healthy women with a family history of cancer.

Materials and methods. Results of NGS testing (26-gene panel) on peripheral blood from 291 women were retrospectively analyzed. Participants were divided into 2 groups: 1 – patients with a history of BC (n = 146); 2 – women with 1^st/2^nd degree relatives diagnosed with BC or ovarian cancer (n = 145).

Results. PVs were 2.5 times more frequent in Group 1 (21.2%) vs Group 2 (8.3%), р = 0,0012. BC onset with PVs occurred earlier than in women in whom significant genetic variants were not identified (39.3 ± 1 vs 44 ± 0,9 years, р = 0,01). PV in the BRCA1,2 genes were detected in 14.3% of group 1 and 6.2% of group 2, respectively. The most frequently detected variants were. BRCA1,2 PVs were most frequent (14.3% Grp1, 6.2% Grp2); Most common PVs were in BRCA1: c.5266dupC, c.4035delA. BRCA1,2 PVs comprised only 68,18% of all PVs, confirming importance of testing other genes. CHEK2 PVs were frequent in Group 1 (4.8%), 7 times higher than Group 2 (р = 0,0076). CHEK2:c.1100delC comprised 57% of these. 20.4% were VUS (variants of uncertain significance), often in non-BRCA genes. PVs in Group 2 were 8 times higher than general population rates.

Conclusion. NGS enables detection of a full spectrum of clinically significant variants, requiring high expertise for interpretation.

1. Sedeta ET, Jobre B, Avezbakiyev B. Breast cancer: Global patterns of incidence, mortality, and trends. Am Soc Clin Oncol. 2023;41(16 Suppl.):10528. https://doi.org/10.1200/JCO.2023.41.16_suppl.10528.

2. Каприн АД, Старинский ВВ, Шахзадова АО (ред.). Злокачественные ново­ образования в России в 2023 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России; 2024. 256 с. Режим доступа: https://oncology-association.ru/wp-content/uploads/2024/08/zis-2023-elektronnaya-versiya.pdf.

3. Daly MB, Pal T, Maxwell KN, Churpek J, Kohlmann W, AlHilli Z et al. NCCN guidelines® insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2024: featured updates to the NCCN guidelines. J Natl Compr Cancer Netw. 2023;21(10):1000–1010. https://doi.org/10.6004/jnccn.2023.0051.

4. Hu C, Hart SN, Gnanaolivu R, Huang H, Lee KY, Na J et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med. 2021;384(5):440–451. https://doi.org/10.1056/NEJMoa2005936.

5. Dorling L, Carvalho S, Allen J, Gonzalez-Neira A, Luccarini C, Wahlstrom C et al. Breast cancer risk genes – association analysis in more than 113,000 women. N Engl J Med. 2021;384(5):428–439. https://doi.org/10.1056/NEJMoa1913948.

6. Buys SS, Sandbach JF, Gammon A, Patel G, Kidd J, Brown KL et al. A study of over 35,000 women with breast cancer tested with a 25‐gene panel of hereditary cancer genes. Cancer. 2017;123(10):1721–1730. https://doi.org/10.1002/cncr.30498.

7. Walsh T, Lee MK, Casadei S, Thornton AM, Stray SM, Pennil C et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci. 2010;107(28):12629–12633. https://doi.org/10.1073/pnas.1007983107.

8. Sokolenko AP, Sokolova TN, Ni VI, Preobrazhenskaya EV, Iyevleva AG, Aleksakhina SN 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. 2020;184(1):229–235. https://doi.org/10.1007/s10549-020-05827-8.

9. Kechin A, Boyarskikh U, Barinov A, Tanas A, Kazakova S, Zhevlova A et al. A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia. Breast Cancer Res Treat. 2023;197(2):387–395. https://doi.org/10.1007/s10549-022-06782-2.

10. Семиглазов ВФ, Кривотько ПВ, Семиглазов ВВ, Дашян ГА, Палтуев РМ. Рекомендации для врачей по ведению пациентов с раком молочной железы. М.: Группа Ремедиум; 2017. 247 с. Режим доступа: https://www.med-sovet.pro/jour/manager/files/RMG_2017_lite.pdf.

11. van Marcke C, Collard A, Vikkula M, Duhoux FP. Prevalence of pathogenic variants and variants of unknown significance in patients at high risk of breast cancer: A systematic review and meta-analysis of gene-panel data. Crit Rev Oncol Hematol. 2018;132:138–144. https://doi.org/10.1016/j.critrevonc.2018.09.009.

12. Francies FZ, Hull R, Khanyile R, Dlamini Z. Breast cancer in low-middle income countries: abnormality in splicing and lack of targeted treatment options. Am J Cancer Res. 2020;10(5):1568–1591. Available at: https://pubmed.ncbi.nlm.nih.gov/32509398/.

13. Grushina TI, Orlov II, Zhavoronkova VV. Correction of comorbidity as part of the pre-rehabilitation of breast cancer patients. Vestnik of Novgorod State University. Series: Medical Sciences. 2022;(1):103–107. (In Russ.) https://doi.org/10.34680/2076-8052.2022.1(126).103-107.

14. Sopik V. International variation in breast cancer incidence and mortality in young women. Breast Cancer Res Treat. 2021;186(2):497–507. https://doi.org/10.1007/s10549-020-06003-8.

15. Golotyuk MA, Berezhnoy AA, Kazantseva NV, Dorofeev AV, Shevchenko SA, Borzunov IV, Rozhkova NI. The clinical and diagnostic characteristics of BRCA-associated breast cancer. P.A. Herzen Journal of Oncolody. 2022:11(6):18–25. (In Russ.) https://doi.org/10.17116/onkolog20221106118.

16. Risch HA, McLaughlin JR, Cole DEC, Rosen B, Bradley L, Fan I et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin–cohort study in Ontario, Canada. J Natl Cancer Inst. 2006;98(23):1694–1706. https://doi.org/10.1093/jnci/djj465.

17. de Oliveira Ferreira C, Carneiro VCG, Araujo Mariz C. Germline mutations in BRCA1 and BRCA2 among Brazilian women with ovarian cancer treated in the Public Health System. BMC Cancer. 2024;24(1):499. https://doi.org/10.1186/s12885-024-12246-1.

18. Stroganova AM, Pospekhova NI, Golovina DA, Cherepanova And S., Dranko SL, Filippova MG. Review of the results of mass screening for the BRCA1/2 gene mutations in patients with different types of malignant neoplasms. RMJ. Medical Review. 2022;6(6):297–308 (In Russ.) https://doi.org/10.32364/2587-6821-2022-6-6-297-308.

19. Gervas PA, Molokov AYu, Panpherova EV, Pisareva LP, Cherdyntseva NV. Ethnic aspects of hereditary breast cancer. Siberian Journal of Oncology. 2019;18(2):102–108. (In Russ.) https://doi.org/10.21294/1814-4861-2019-18-2-102-108.

20. Feszak S, Feszak IJ, Kluźniak W, Wokołorczyk D, Stempa K, Gliniewicz K et al. BRCA1 and BRCA2 Mutations in Polish Women with Ductal Carcinoma In Situ. Cancers. 2025;17(4):613. https://doi.org/10.3390/cancers17040613.

21. Cybulski C, Kluźniak W, Huzarski T, Wokołorczyk D, Kashyap A, Rusak B et al. The spectrum of mutations predisposing to familial breast cancer in Poland. Int J Cancer. 2019;145(12):3311–3320. https://doi.org/10.1002/ijc.32492.

22. Shumilova S, Danishevich A, Nikolaev S, Krasnov G, Ikonnikova A, Isaeva D et al. High-and Moderate-Risk Variants Among Breast Cancer Patients and Healthy Donors Enrolled in Multigene Panel Testing in a Population of Central Russia. Int J Mol Sci. 2024;25(23):12640. https://doi.org/10.3390/ijms252312640.

23. Peng Y, Liao J, He X, Zhou Y, Zhang L, Jia Y, Yang H. Prevalence of BRCA1 and BRCA2 mutations in ovarian cancer patients from Yunnan Province in southwest China. Eur J Cancer Prev. 2025;34(3):231–240. https://doi.org/10.1097/CEJ.0000000000000931.

24. Kluz T, Jasiewicz A, Marczyk E, Jach R, Jakubowska A, Lubiński J, Narod SA, Gronwald J. Frequency of BRCA1 and BRCA2 causative founder variants in ovarian cancer patients in South-East Poland. Hered Cancer Clin Pract. 2018;16:6. https://doi.org/10.1186/s13053-018-0089-x.

25. Laitman Y, Friebel TM, Yannoukakos D, Fostira F, Konstantopoulou I, Figlioli G et al. The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries. Hum Mutat. 2019;40(11):e1–e23. https://doi.org/10.1002/humu.23842.

26. Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018;39(5):593–620. https://doi.org/10.1002/humu.23406.

27. Pavlovica K, Irmejs A, Noukas M, Palover M, Kals M, Tonisson N et al. Spectrum and frequency of CHEK2 variants in breast cancer affected and general population in the Baltic states region, initial results and literature review. Eur J Med Genet. 2022;65(5):104477. https://doi.org/10.1016/j.ejmg.2022.104477.

28. Yadav S, Boddicker NJ, Na J, Polley EC, Hu C, Hart SN et al. Contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. J Clin Oncol. 2023;41(9):1703–1713. https://doi.org/10.1200/JCO.22.01239.

29. Cheremokhin DA, Deryabina SS, Bikbulatova ER, Knysh OE, Kudryavtseva EV. CHEK2 gene mutations and their role in breast carcinogenesis. Women’s Health and Reproduction. 2025;(1):27–35. (In Russ.) Available at: https://journalgynecology.ru/statyi/mutacii-gena-chek2-i-ih-rol-v-kancerogeneze-molochnoj-zhelezy.

30. Nasedkina TV, Gromyko OE, Emelyanova MA, Ignatova EO, Kazubskaya TP, Portnoi SM et al. Genotyping of BRCA1, BRCA2, and CHEK2 germline mutations in Russian breast cancer patients using diagnostic biochips. Mol Biol. 2014;48(2):243–250. https://doi.org/10.1134/S0026893314020149.

31. Boonen RACM, Wiegant WW, Celosse N, Vroling B, Heijl S, Kote-Jarai Z et al. Functional analysis identifies damaging CHEK2 missense variants associated with increased cancer risk. Cancer Res. 2022;82(4):615–631. https://doi.org/10.1158/0008-5472.CAN-21-1845.

32. Abdel-Razeq H, Tamimi F, Abujamous L, Abdel-Razeq R, Abunasser M, Edaily S et al. Rates of Variants of Uncertain Significance Among Patients With Breast Cancer Undergoing Genetic Testing: Regional Perspectives. Front Oncol. 2022;12:673094. https://doi.org/10.3389/fonc.2022.673094.

33. de Moor JS, Gray SW, Mitchell SA, Klabunde CN, Freedman AN. Oncologist confidence in genomic testing and implications for using multimarker tumor panel tests in practice. JCO Precis Oncol. 2020;4:620–631. https://doi.org/10.1200/PO.19.00338.

34. Esterling L, Wijayatunge R, Brown K, Morris B, Hughes E, Pruss D et al. Impact of a Cancer Gene Variant Reclassification Program Over a 20-Year Period. JCO Precis Oncol. 2020;4:944–954. https://doi.org/10.1200/PO.20.00020.

35. Abdel-Razeq H, Abujamous L, Al-Azzam K, Abu-Fares H, Bani Hani H, Alkyam M et al. Guideline-Based, Multi-Gene Panel Germline Genetic Testing for at-Risk Patients with Breast Cancer. Breast Cancer. 2023;15:1–10. https://doi.org/10.2147/BCTT.S394092.

36. Samadder NJ, Riegert-Johnson D, Boardman L, Rhodes D, Wick M, Okuno S et al. Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome. JAMA Oncol. 2021;7(2):230–237. https://doi.org/10.1001/jamaoncol.2020.6252.

37. Sokolenko AP, Iyevleva AG, Mitiushkina NV, Suspitsin EN, Preobrazhenskaya EV, Kuligina ES et al Hereditary breast-ovarian cancer syndrome in Russia. Acta Naturae. 2010;2(4):31–35. https://doi.org/10.32607/20758251-2010-2-4-31-35.

38. Bateneva YeI, Filippova MG, Tyulyandina AS, Meshcheryakov AA, Zhordania KI, Gritsai AN et al. High rate of mutations in the BRCA1, BRCA2, CHEK2, NBN, and BLM genes in Russian ovarian cancer patients. Opuholi Zenskoj Reproduktivnoj Sistemy. 2014;(4):51–56. (In Russ.) https://doi.org/10.17650/1994-4098-2014-0-4-51-56.