Germline Screening of Cancer-Related Genes in Turkish Ovarian Cancer Patients

Year 2022, , 181 - 187, 31.12.2022

Esra Arslan Ateş , Ceren Alavanda , Bilgen Bilge Geçkinli , İlter Güney , Tuba Gunel

https://doi.org/10.26650/experimed.1187969

Abstract

Objective: Ovarian cancer (OC) is one of the most fatal types of cancer and affects 1%-1.5% of women worldwide. The most common genes causing OC are the BRCA1 and BRCA2 genes. However, improvements in next-generation sequencing (NGS) technologies have allowed for screening of the various genes related to hereditary cancer syndromes. The aim of this study was to evaluate cancer-related gene variations among cases of ovarian cancer.

Materials and Methods: The study evaluated 63 cases that were referred to the Marmara University Pendik Training and Research Hospital Genetic Diseases Diagnostic Center between 2016-2021 with a diagnosis of OC for germline variations in 25 cancer-related genes using NGS. Large intragenic rearrangements of the BRCA1 and BRCA2 genes were screened using multiplex ligation-dependent probe amplification (MLPA).

Results: The study detected 12 distinct pathogenic variations in the BRCA1, BRCA2, BRIP1, and RAD50 genes in 13 OC cases. Four of the 13 cases involved copy number variations that included at least one exon of the BRCA1 gene.

Conclusion: This study detected pathogenic BRCA1 variations to be the leading cause of hereditary OC. The study showed just screening for BRCA1 to reveal the underlying hereditary defect in 76.9% of the cases, which seems higher compared to literature. More studies involving larger cohorts are necessary to figure out the exact frequency of BRCA1 variations in Turkish OC cases

Keywords

Ovarian Cancer, hereditary cancer syndromes, Germline Mutation

References

• 1. Stewart C, Ralyea C, Lockwood S. Ovarian cancer: An integrated review. Semin Oncol Nurs 2019; 35(2): 151-6. [CrossRef] google scholar
• 2. Webb PM, Jordan SJ. Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol 2017; 41: 3-14. [CrossRef] google scholar
• 3. Eccles DM, Balmana J, Clune J, Ehlken B, Gohlke A, Hirst C, et al. Selecting patients with ovarian cancer for germline brca mutation testing: Findings from guidelines and a systematic literature review. Adv Ther 2016; 33(2): 129-50. [CrossRef] google scholar
• 4. Shanbhogue KP, Prasad AS, Ucisik-Keser FE, Katabathina VS, Morani AC. Hereditary ovarian tumour syndromes: Current update on genetics and imaging. Clin Radiol 2021; 76(4): 313e315-313 e326. [CrossRef] google scholar
• 5. Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, et al. Hereditary ovarian cancer: Not only BRCA 1 and 2 genes. Biomed Res Int 2015; 2015: 341723. [CrossRef] google scholar
• 6. Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24 Suppl 6:vi24-32. [CrossRef] google scholar
• 7. Fierheller CT, Alenezi WM, Tonin PN. The Genetic analyses of French Canadians of Quebec facilitate the characterization of new cancer predisposing genes implicated in hereditary breast and/ or ovarian cancer syndrome families. Cancers (Basel) 2021; 13(14). [CrossRef] google scholar
• 8. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17(5): 405-24. [CrossRef] google scholar
• 9. Arslan Ates E, Turkyilmaz A, Alavanda C, Yildirim O, Guney AI. Multigene panel testing in Turkish hereditary cancer syndrome patients. Medeni Med J 2022; 37(2): 150-8. [CrossRef] google scholar
• 10. La Vecchia C. Ovarian cancer: Epidemiology and risk factors. Eur J Cancer Prev 2017; 26(1): 55-62. [CrossRef] google scholar
• 11. Zheng G, Yu H, Kanerva A, Forsti A, Sundquist K, Hemminki K. Familial ovarian cancer clusters with other cancers. Sci Rep 2018; 8(1): 11561. [CrossRef] google scholar
• 12. Yazici H, Glendon G, Burnie SJ, Saip P, Buyru F, Bengisu E, et al. BRCA1 and BRCA2 mutations in Turkish familial and non-familial ovarian cancer patients: A high incidence of mutations in non-familial cases. Hum Mutat 2002; 20(1): 28-34. [CrossRef] google scholar
• 13. Demir S, Tozkir H, Gurkan H, Atli EI, Yalcintepe S, Atli E, et al. Genetic screening results of individuals with high risk BRCA-related breast/ovarian cancer in Trakya region of Turkey. J BUON 2020; 25(3): 1337-47. google scholar
• 14. 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(1): 934. [CrossRef] google scholar
• 15. 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(2): 353-7. [CrossRef] google scholar
• 16. 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(1): 131-5. [CrossRef] google scholar
• 17. Yazici H, Kilic S, Akdeniz D, Sukruoglu O, Tuncer SB, Avsar 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(2): 93-9. [CrossRef] google scholar
• 18. Minion LE, Dolinsky JS, Chase DM, Dunlop CL, Chao EC, Monk BJ. Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2. Gynecol Oncol 2015; 137(1): 86-92. [CrossRef] google scholar
• 19. Cantor S, Drapkin R, Zhang F, Lin Y, Han J, Pamidi S, et al. The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc Natl Acad Sci USA 2004; 101(8): 2357-62. [CrossRef] google scholar
• 20. Waltes R, Kalb R, Gatei M, Kijas AW, Stumm M, Sobeck A, et al. Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. Am J Hum Genet 2009; 84(5): 605-16. [CrossRef] google scholar
• 21. Del Valle J, Rofes P, Moreno-Cabrera JM, Lopez-Doriga A, Belhadj S, Vargas-Parra G, et al. Exploring the role of mutations in fanconi anemia genes in hereditary cancer patients. Cancers (Basel) 2020; 12(4). [CrossRef] google scholar