Epitelyal Over Kanserlerinde Genetik Testler

Yıl 2025, Cilt: 25 Sayı: 2, 66 - 75, 11.09.2025

Tevfik Güvenal , Fuat Demirkıran , İlkkan Dünder

Öz

Epitalyal over kanserleri için en bilinen risk faktörü aile öyküsü ve genetik mutasyonların varlığıdır. Genetik mutasyonların en bilineni BRCA1 ve 2 gen mutasyonları olup bunlar homolog rekombinasyon onarım gen ailesindendir. Ayrıca BRCA1-2 dışında homolog rekombinasyon onarımında görevli diğer gen mutasyonları da risk faktörü oluşturmaktadır. Gen mutasyonları germ line ve/veya somatik mutasyonlar şeklinde olmaktadır. Günümüzde epitelyal over kanserlerinde, özellikle yüksek dereceli seröz tümörlerde bu mutasyonların bilinmesi, hem hastanın tedavasinin yönlendirilmesinde hem de aile bireylerinde risk olup olmadığının belirlenmesinde önemlidir. Bu derlemede bu testlerin saptanma yöntemleri, tedavi seçminde etkinliği ve riskli kadınlardaki yönetim tartışılacaktır.

Anahtar Kelimeler

Epitelyal over kanseri , genetik testler , BRCA1 , BRCAA2 , homolog rekombinasyon onarım.

Destekleyen Kurum

Türk Jinekolojik Onkoloji Derneği

Kaynakça

• 1. https://gco.iarc.fr/today/home
• 2. American Cancer Society: Key statistics for ovarian cancer. https://www.cancer.org/cancer/ovarian-cancer/ about/key-statistics.html
• 3. https://gco.iarc.fr/today/online-analysis-map?
• 4. Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci USA. 2011;108:18032–7.
• 5. Vasen HF, Moslein G, Alonso A, Bernstein I, Bertario L, Blanco I, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007;44(6):353e62.
• 6. Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30:2654–63.
• 7. Norquist B, Wurz KA, Pennil CC, et al: Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol 29:3008-3015, 2011
• 8. Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20:764–75.
• 9. Zhang S, Royer R, Li S, et al: Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol 121:353-357, 2011
• 10. Abeliovich D, Kaduri L, Lerer I, Weinberg N, Amir G, Sagi M, et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet 1997;60(3):505e14.
• 11. George A, Riddell D, Seal S, Talukdar S, Mahamdallie S, Ruark E, et al. Implementing rapid, robust, cost-effective, patient- centred, routine genetic testing in ovarian cancer patients. Sci Rep 2016;6:29506.
• 12. Norquist BM, Pennington KP, Agnew KJ, Harrell MI, Pennil CC, Lee MK, et al. Characteristics of women with ovarian car- cinoma who have BRCA1 and BRCA2 mutations not identified by clinical testing. Gynecol Oncol 2013;128(3):483-7.
• 13. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.
• 14. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov 2015; 5(11): 1137–1154.
• 15. Takaya H, Nakai H, Takamatsu S, Mandai M & Matsumura N. Homologous recombination deficiency status-based classification of high-grade serous ovarian carcinoma. www.nature.com/scientificreports (2020) 10:2757
• 16. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154–64.
• 17. Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495–505.
• 18. Ray-Coquard IL, Pautier P, Pignata S, et al: Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev. Ann Oncol 30, 2019 (suppl 5; abstr LBA2_PR)
• 19. Gonzalez-Mart ́ınA, Pothuri B, VergoteI ,et al: Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 10.1056/NEJMoa1910962 (epub ahead of print on September 28, 2019] 2019
• 20. Coleman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, et al. Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. N Engl J Med. 2019 Dec 19;381(25):2403-2415
• 21. Knabben, L., Imboden, S., & Mueller, M. D. (2019). Genetic testing in ovarian cancer – clinical impact and current practices. Hormone Molecular Biology and Clinical Investigation, 0(0). doi:10.1515/hmbci-2019-0025
• 22. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382–92.
• 23. Ledermann JA, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving Olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol. 2016;17:1579– 89.
• 24. Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, et al. SOLO2/ENGOT-Ov21 investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274–84.
• 25. Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo- controlled, phase 3 trial. Lancet. 2017;390:1949–61.
• 26. Petrillo M, Marchetti C, De Leo R, Musella A, Capoluongo E, Paris I, et al. BRCA mutational status, initial disease presentation, and clinical outcome in high-grade serous advanced ovarian cancer: a multicenter study. Am J Obstet Gynecol. 2017;217:334.e1–e9.
• 27. Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, Ramus SJ, Karlan BY, et al. kConFab Investigators; Cancer Genome Atlas Research Network. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. J Am Med Assoc. 2012;307:382–90.
• 28. Harter P, Johnson T, Berton-Rigaud D, Park SY, Friedlander M, Del Campo JM, et al. BRCA1/2 mutations associated with progression-free survival in ovarian cancer patients in the AGO-OVAR 16 study. Gynecol Oncol. 2016;140:443–9.
• 29. Moyer VA, US Preventive Services Task Force: Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 160:271-281, 2014
• 30. Frey MK, Pothuri B. Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature. Gynecol Oncol Res Pract. 2017 Feb 22;4:4. doi: 10.1186/s40661-017-0039-8.
• 31. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in patients with platinum- sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15:852-861, 2014
• 32. Plon, S.E., Eccles, D.M., Easton, D., et al., 2008. Sequence variant classification and re- porting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum. Mutat. 29, 1282–1291.
• 33. Bell D, Berchuck A, Chien J et al. Integrated genomic analyses of ovaran carcinoma. Nature 2011; 474(7353): 609–615.
• 34. Jensen KC, Mariappan MR, Putcha GV, et al: Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger. Am J Surg Pathol 32:1029- 1037, 2008
• 35. Murphy MA, Wentzensen N: Frequency of mismatch repair deficiency in ovarian cancer: A systematic review— This article is a US Government work and, as such, is in the public domain of the United States of America. Int J Cancer 129:1914-1922, 2011
• 36. Pal T, Permuth-Wey J, Kumar A, et al: Systematic review and meta-analysis of ovarian cancers: Estimation of microsatellite-high frequency and charac- terization of mismatch repair deficient tumor histology. Clin Cancer Res 14:6847-6854, 2008
• 37. Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Am Med Assoc. 2017;317:2402–16.
• 38. Konstantinopoulos PA, Norquist B, Lacchetti C, Armstrong D, Grisham RN, Goodfellow PJ, Kohn EC, Levine DA, Liu JF, Lu KH, Sparacio D, Annunziata CM. Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline. J Clin Oncol. 2020 Apr 10;38(11):1222- 1245.