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Frequency and distribution of BRCA1/BRCA2 large genomic rearrangements in Turkish population with breast cancer

Journal of Human Genetics volume 68, pages 485–490 (2023)Cite this article

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Abstract

Germline mutations in BRCA1 and BRCA2 genes are mainly responsible for breast and/or ovarian cancer patients. Most of the mutations in these genes are single nucleotide changes or deletions/insertions of small numbers of bases, while a minority of mutations in these genes are large genomic rearrangements (LGRs). The frequency of LGRs in the Turkish population is not clearly known. Also insufficient awareness of the importance of LGRs in breast and/or ovarian cancer development can lead to some disruptions in patient management. So, we aimed to determine the frequency and distribution of the LGRs in the BRCA1/2 genes in the Turkish population. We investigated rearrangements of BRCA genes using multiplex ligation-dependent probe amplification (MLPA) analysis in 1540 patients with a personal and/or family history of breast and/or ovarian cancer or who had familial known large deletion/duplication and applied for segregation. The estimated overall frequency of LGRs in our group was 3,4% (52/1540) with 91% in BRCA1 gene and 9% in BRCA2 gene. 13 different rearrangements were detected (10 BRCA1, 3 BRCA2). To the best our knowledge, BRCA1 exon 1–16 duplication and BRCA2 exon 6 deletion have not been previously reported before. Our study results supported that the detection of rearrangements in BRCA genes is of great importance and it should be planned routinely in patients whose mutations cannot be detected by sequence analysis in screening programs.

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References

  1. saglik.gov.tr. Turkey: Health Statistics Yearbook; 2019. https://dosyasb.saglik.gov.tr/Eklenti/40566,health-statistics-yearbook-2019pdf.pdf?0.

  2. Mehrgou A, Akouchekian M. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Iran. 2016;30:369.

    PubMed  PubMed Central  Google Scholar 

  3. Lux MP, et al. Hereditary breast and ovarian cancer: review and future perspectives. J Mol Med. 2006;84:16–28.

    Article  PubMed  Google Scholar 

  4. Kwong A, Chen J, Shin VY, Ho JC, Law FB, Au CH, et al. The importance of analysis of long-range rearrangement of BRCA1 and BRCA2 in genetic diagnosis of familial breast cancer. Cancer Genet. 2015;208:448–54.

    Article  CAS  PubMed  Google Scholar 

  5. Riahi A, Chabouni-Bouhamed H, Kharrat M. Prevalence of BRCA1 and BRCA2 large genomic rearrangements in Tunisian high risk breast/ovarian cancer families: Implications for genetic testing. Cancer Genet. 2017;210:22–27.

    Article  CAS  PubMed  Google Scholar 

  6. Palacios J, Robles-Frías MJ, Castilla MA, López-García MA, Benítez J. The molecular pathology of hereditary breast cancer. Pathobiology. 2008;75:85–94.

    Article  CAS  PubMed  Google Scholar 

  7. Kobayashi H, Ohno S, Sasaki Y, Matsuura M. Hereditary breast and ovarian cancer susceptibility genes (review). Oncol Rep. 2013;30:1019–29.

    Article  CAS  PubMed  Google Scholar 

  8. Larsen MJ, Thomassen M, Gerdes AM, Kruse TA. Hereditary breast cancer: clinical, pathological and molecular characteristics. Breast Cancer. 2014;8:145–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Judkins T, Rosenthal E, Arnell C, Burbidge LA, Geary W, Barrus T, et al. Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer. 2012;118:5210–6.

    Article  CAS  PubMed  Google Scholar 

  10. Marshall M, Solomon S. Hereditary breast-ovarian cancer: clinical findings and medical management. Plast Surg Nurs. 2007;27:124–7.

    Article  PubMed  Google Scholar 

  11. McVeigh TP, Cody N, Carroll C, Duff M, Farrell M, Bradley L, et al. Recurrent large genomic rearrangements in BRCA1 and BRCA2 in an Irish case series. Cancer Genet. 2017;214-215:1–8.

    Article  CAS  PubMed  Google Scholar 

  12. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  13. Cecener G, Sabour Takanlou L, Sabour Takanlou M, Egeli U, Eskiler GG, Aksoy S, et al. Clinicopathologic features and genetic characteristics of the BRCA1/2 mutation in Turkish breast cancer patients. Cancer Genet. 2020;240:23–32.

    Article  CAS  PubMed  Google Scholar 

  14. del Valle J, Feliubadaló L, Nadal M, Teulé A, Miró R, Cuesta R, et al. Identification and comprehensive characterization of large genomic rearrangements in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat. 2010;122:733–43.

    Article  PubMed  Google Scholar 

  15. Kang P, Mariapun S, Phuah SY, Lim LS, Liu J, Yoon SY, et al. Large BRCA1 and BRCA2 genomic rearrangements in Malaysian high risk breast-ovarian cancer families. Breast Cancer Res Treat. 2010;124:579–84.

    Article  CAS  PubMed  Google Scholar 

  16. Vasickova P, Machackova E, Lukesova M, Damborsky J, Horky O, Pavlu H, et al. High occurrence of BRCA1 intragenic rearrangements in hereditary breast and ovarian cancer syndrome in the Czech Republic. BMC Med Genet. 2007;8:32.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Maistro S, Teixeira N, Encinas G, Katayama ML, Niewiadonski VD, Cabral LG, et al. Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil. BMC Cancer. 2016;16:934.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, 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. Am J Hum Genet. 2003;72:1117–30. https://doi.org/10.1086/375033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hansen TV, Jønson L, Albrechtsen A, Andersen MK, Ejlertsen B, Nielsen FC. Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families. Breast Cancer Res Treat. 2009;115:315–23.

    Article  CAS  PubMed  Google Scholar 

  20. Gutiérrez-Enríquez S, de la Hoya M, Martínez-Bouzas C, Sanchez de Abajo A, Ramón YCT, Llort G, et al. Screening for large rearrangements of the BRCA2 gene in Spanish families with breast/ovarian cancer. Breast Cancer Res Treat. 2007;103:103–7.

    Article  PubMed  Google Scholar 

  21. Preisler-Adams S, Schönbuchner I, Fiebig B, Welling B, Dworniczak B, Weber BH. Gross rearrangements in BRCA1 but not BRCA2 play a notable role in predisposition to breast and ovarian cancer in high-risk families of German origin. Cancer Genet Cytogenet. 2006;168:44–9.

    Article  CAS  PubMed  Google Scholar 

  22. Gad S, Caux-Moncoutier V, Pagès-Berhouet S, Gauthier-Villars M, Coupier I, Pujol P, et al. Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families. Oncogene. 2002;21:6841–7.

    Article  CAS  PubMed  Google Scholar 

  23. Aydin F, Akagun T, Yildiz B, Fidan E, Ozdemir F, Kavgaci H. Clinicopathologic characteristics and BRCA-1/BRCA-2 mutations of Turkish patients with breast cancer. Bratisl Lek Listy. 2011;112:521–3.

    CAS  PubMed  Google Scholar 

  24. Yazıcı H, Kılıç S, Akdeniz D, Şükrüoğlu Ö, Tuncer ŞB, Avşar M, et al. Frequency of rearrangements versus small indels mutations in BRCA1 and BRCA2 genes in Turkish patients with high risk breast and ovarian cancer. Eur J Breast Health. 2018;14:93–99.

    PubMed  PubMed Central  Google Scholar 

  25. Aktas D, Gultekin M, Kabacam S, Alikasifoglu M, Turan AT, Tulunay G, et al. Identification of point mutations and large rearrangements in the BRCA1 gene in 667 Turkish unselected ovarian cancer patients. Gynecol Oncol. 2010;119:131–5.

    Article  CAS  PubMed  Google Scholar 

  26. Ewald IP, Ribeiro PL, Palmero EI, Cossio SL, Giugliani R, Ashton-Prolla P. Genomic rearrangements in BRCA1 and BRCA2: a literature review. Genet Mol Biol. 2009;32:437–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Smith MJ, Urquhart JE, Harkness EF, Miles EK, Bowers NL, Byers HJ, et al. The contribution of whole gene deletions and large rearrangements to the mutation spectrum in inherited tumor predisposing syndromes. Hum Mutat. 2016;37:250–6.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. Peixoto A, Pinheiro M, Massena L, Santos C, Pinto P, Rocha P, et al. Genomic characterization of two large Alu-mediated rearrangements of the BRCA1 gene. J Hum Genet. 2013;58:78–83.

    Article  CAS  PubMed  Google Scholar 

  30. Engert S, Wappenschmidt B, Betz B, Kast K, Kutsche M, Hellebrand H, et al. MLPA screening in the BRCA1 gene from 1,506 German hereditary breast cancer cases: novel deletions, frequent involvement of exon 17, and occurrence in single early-onset cases. Hum Mutat. 2008;29:948–58.

    Article  CAS  PubMed  Google Scholar 

  31. Buffone A, Capalbo C, Ricevuto E, Sidoni T, Ottini L, Falchetti M, et al. Prevalence of BRCA1 and BRCA2 genomic rearrangements in a cohort of consecutive Italian breast and/or ovarian cancer families. Breast Cancer Res Treat. 2007;106:289–96.

    Article  CAS  PubMed  Google Scholar 

  32. Montagna M, Dalla Palma M, Menin C, Agata S, De Nicolo A, Chieco-Bianchi L, et al. Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. Hum Mol Genet. 2003;12:1055–61.

    Article  CAS  PubMed  Google Scholar 

  33. Arnold AG, Otegbeye E, Fleischut MH, Glogowski EA, Siegel B, Boyar SR, et al. Assessment of individuals with BRCA1 and BRCA2 large rearrangements in high-risk breast and ovarian cancer families. Breast Cancer Res Treat. 2014;145:625–34. https://doi.org/10.1007/s10549-014-2987-6.

    Article  CAS  PubMed  Google Scholar 

  34. Armaou S, Konstantopoulou I, Anagnostopoulos T, Razis E, Boukovinas I, Xenidis N, et al. Novel genomic rearrangements in the BRCA1 gene detected in Greek breast/ovarian cancer patients. Eur J Cancer. 2007;43:443–53. https://doi.org/10.1016/j.ejca.2006.09.021.

    Article  CAS  PubMed  Google Scholar 

  35. de Juan Jiménez I, García Casado Z, Palanca Suela S, Esteban Cardeñosa E, López Guerrero JA, Segura Huerta Á, et al. Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence. Fam Cancer. 2013;12:767–77.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Genetics, Istanbul Haseki Education and Training Hospital, Istanbul, Turkey

    Tugba Akin Duman & Fatma Nihal Ozturk

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  1. Tugba Akin Duman
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  2. Fatma Nihal Ozturk
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TAD: designed the analyses collected and interpreted data wrote the paper. FNO: designed the analyses collected and interpreted data.

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Correspondence to Tugba Akin Duman.

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Akin Duman, T., Ozturk, F.N. Frequency and distribution of BRCA1/BRCA2 large genomic rearrangements in Turkish population with breast cancer. J Hum Genet 68, 485–490 (2023). https://doi.org/10.1038/s10038-023-01140-6

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