ISSN: 2148-8274 / E-ISSN: 2587-0084
, Türk Üreme Tıbbı ve Cerrahisi
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Turkish Journal of Reproductive Medicine and Surgery

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BRCA Gen Mutasyonları ve Fertilite
BRCA Gene Mutations and Fertility
Received Date : 08 Dec 2020
Accepted Date : 06 Jan 2021
Available Online : 03 Feb 2021
Doi: 10.24074/tjrms.2020-80482 - Makale Dili: TR
TJRMS. 2020;4(2):64-72
ÖZET
Meme kanseri duyarlılık genlerinde (BRCA1-BRCA2) mutasyon taşıyan kadınlarda yaşam boyu meme ve over kanseri geliştirme riski artmıştır. Bu mutasyonları taşıyan genç kadınlarda üremeye ilişkin konular da klinik yaklaşımda önemlidir. Risk azaltıcı salpingo-ooferektomi önerisi ve meme kanseri ve ilişkili gonadotoksik tedavilerle yüzleşme riski olguların aile planlaması konusunda kararlarını etkileyebilmektedir. BRCA genleri temel olarak tümör baskılayıcı genler olarak görev alırlar ve DNA çift sarmal kırık tamirinde önemli rol oynamaktadırlar. Yetersiz gen fonksiyonuna bağlı DNA çift sarmal kırık tamirinde bozulma, hücrelerde DNA hasar birikimine bağlı olarak karsinojenik transformasyon veya apoptozise neden olmaktadır. BRCA gen mutasyonlarının over rezervi ve fertilite üzerine etkileri çeşitli preklinik ve klinik çalışmalarla araştırılmıştır. Güncel literatürde tartışmalı sonuçlar olmakla birlikte, özellikle BRCA1 gen mutasyonları ile azalmış ovaryan rezerv arasında olası bir bağlantıya işaret eden invivo/invitro araştırmalar ve klinik gözlemsel çalışmalar bulunmaktadır. BRCA geni ve DNA tamir mekanizmasının over rezervi üzerine etkileri ile ilgili ileri çalışmaların sonuçları oldukça dikkat çekicidir. Erken menapoz yaşı, düşük serum anti-Müllerian hormon (AMH) düzeyleri ve invitro fertilizasyon sikluslarındaki ovaryan stimülasyona zayıf cevap varlığı da çeşitli klinik çalışmalarda rapor edilmiştir. Bu makalede, BRCA gen mutasyonları ile ovaryan rezerv ve fertilite arasında olası ilişkiyi araştıran güncel çalışmaların gözden geçirilmesi amaçlanmıştır.
ABSTRACT
Women who carry breast cancer susceptibility gene mutations (BRCA1 or BRCA2) have an increased life-time risk of developing breast and ovarian cancer. The reproductive issues of the young women who carry these mutations are also important for the clinical management. The recommendation of risk reducing salpingo-oophorectomy, and the risk of facing with breast cancer and related gonadotoxic treatments may affect their decision on family planning issues. BRCA genes mainly act as a tumor suppressor gene and play an integral role on DNA double strand break repair mechanism. Impairment of the DNA double strand break repair due to insufficient function in genes has been associated with carcinogenic transformation or apoptosis in cells through accumulation of DNA damage. The role of BRCA gene mutations on ovarian reserve and fertility has been explored by a several preclinic and clinical studies. Although controversies exist in the current literature, there are invivo/invitro research and also clinical observational studies which indicate a possible association between mainly BRCA1 gene mutations and reduced ovarian reserve. The results of further studies which exploring the effects of BRCA gene and DNA repair mechanism on ovarian reserve are remarkable. Early age at menopause, decreased serum anti-Mullerian hormone (AMH) levels and reduced response to ovarian stimulation in invitro fertilization cycles have been also reported in several clinical studies. The aim of this article is to review the current studies exploring the possible association between BRCA gene mutations with ovarian reserve and fertility.
REFERANSLAR
  1. Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci. 2004;95(11):866-71.[Crossref] [PubMed] 
  2. Daum H, Peretz T, Laufer N. BRCA mutations and reproduction. Fertil Steril 2018; 109:33-8.[Crossref] [PubMed] 
  3. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071-8.[Crossref] [PubMed] [PMC] 
  4. Lambertini M, Goldrat O, Ferreira AR, et al. Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients. Ann Oncol. 2018;29(1):237-243.[Crossref] [PubMed] 
  5. Kuchenbaecker KB, Hopper JL, Barnes DR et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017;317(23):2402-16.[Crossref] [PubMed] 
  6. Krassuski L, Vennedey V, Stock S, Kautz-Freimuth S. Effectiveness of decision aids for female BRCA1 and BRCA2 mutation carriers: a systematic review. BMC Med Inform Decis Mak. 2019;19(1):154.[Crossref] [PubMed] [PMC] 
  7. Helpman L, Zidan O, Friedman E, et al. Young Israeli women with epithelial ovarian cancer: prevalence of BRCA mutations and clinical correlates. J Gynecol Oncol. 2017;28(5):e61.[Crossref] [PubMed] [PMC] 
  8. Oktay K, Kim JY, Barad D, Babayev SN. Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks. J Clin Oncol. 2010;28(2):240-4.[Crossref] [PubMed] [PMC] 
  9. Titus S, Li F, Stobezki R, et al. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci Transl Med. 2013;5(172):172ra21.[Crossref] [PubMed] [PMC] 
  10. Oktay K, Turan V, Titus S, Stobezki R, Liu L. BRCA Mutations, DNA Repair Deficiency, and Ovarian Aging. Biol Reprod. 2015;93(3):67.[Crossref] [PubMed] [PMC] 
  11. Luo Y, Hartford SA, Zeng R, Southard TL, Shima N, Schimenti JC. Hypersensitivity of primordial germ cells to compromised replication-associated DNA repair involves ATM-p53-p21 signaling. PLoS Genet. 2014;10(7):e1004471.[Crossref] [PubMed] [PMC] 
  12. de la Noval BD. Potential implications on female fertility and reproductive lifespan in BRCA germline mutation women. Arch Gynecol Obstet. 2016;294(5):1099-103.[Crossref] [PubMed] 
  13. Finch A, Valentini A, Greenblatt E, et al.; Hereditary Breast Cancer Study Group. Frequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation. Fertil Steril. 2013;99(6):1724-8.[Crossref] [PubMed] 
  14. Lin WT, Beattie M, Chen LM, et al. Comparison of age at natural menopause in BRCA1/2 mutation carriers with a non-clinic-based sample of women in northern California. Cancer. 2013;119(9):1652-9.[Crossref] [PubMed] [PMC] 
  15. Son KA, Lee DY, Choi D. Association of BRCA Mutations and Anti-müllerian Hormone Level in Young Breast Cancer Patients. Front Endocrinol (Lausanne). 2019;10:235.[Crossref] [PubMed] [PMC] 
  16. Wang ET, Pisarska MD, Bresee C, et al. BRCA1 germline mutations may be associated with reduced ovarian reserve. Fertil Steril. 2014;102(6):1723-8.[Crossref] [PubMed] [PMC] 
  17. Phillips KA, Collins IM, Milne RL, et al.; Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab). Anti-Müllerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations. Hum Reprod. 2016;31(5):1126-32.[Crossref] [PubMed] [PMC] 
  18. Derks-Smeets IAP, van Tilborg TC, van Montfoort A, et al. BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD. J Assist Reprod Genet. 2017;34(11):1475-1482.[Crossref] [PubMed] [PMC] 
  19. Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, Górski B, Zielińska D, Tołoczko-Grabarek A. Premature menopause in patients with BRCA1 gene mutation. Breast Cancer Res Treat. 2006;100(1):59-63.[Crossref] [PubMed] 
  20. Giordano S, Garrett-Mayer E, Mittal N, et al. Association of BRCA1 Mutations with Impaired Ovarian Reserve: Connection Between Infertility and Breast/Ovarian Cancer Risk. J Adolesc Young Adult Oncol. 2016;5(4):337-43.[Crossref] [PubMed] [PMC] 
  21. Ben-Aharon I, Levi M, Margel D, et al. Premature ovarian aging in BRCA carriers: a prototype of systemic precocious aging? Oncotarget. 2018;9(22):15931-15941.[Crossref] [PubMed] [PMC] 
  22. Turan V, Bedoschi G, Emirdar V, Moy F, Oktay K. Ovarian Stimulation in Patients With Cancer: Impact of Letrozole and BRCA Mutations on Fertility Preservation Cycle Outcomes. Reprod Sci. 2018;25(1):26-32.[Crossref] [PubMed] 
  23. Porcu E, Cillo GM, Cipriani L, et al. Impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcomes in young women with breast cancer. J Assist Reprod Genet. 2020;37(3):709-15.[Crossref] [PubMed] [PMC] 
  24. Collins IM, Milne RL, McLachlan SA, et al. Do BRCA1 and BRCA2 mutation carriers have earlier natural menopause than their noncarrier relatives? Results from the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer. J Clin Oncol. 2013;31(31):3920-5.[Crossref] [PubMed] 
  25. Lambertini M, Olympios N, Lequesne J, et al. Impact of Taxanes, Endocrine Therapy, and Deleterious Germline BRCA Mutations on Anti-müllerian Hormone Levels in Early Breast Cancer Patients Treated With Anthracycline- and Cyclophosphamide-Based Chemotherapy. Front Oncol. 2019;9:575.[Crossref] [PubMed] [PMC] 
  26. van Tilborg TC, Derks-Smeets IA, Bos AM, et al. Serum AMH levels in healthy women from BRCA1/2 mutated families: are they reduced? Hum Reprod. 2016;31(11):2651-9.[Crossref] [PubMed] 
  27. Michaelson-Cohen R, Mor P, Srebnik N, Beller U, Levy-Lahad E, Eldar-Geva T. BRCA mutation carriers do not have compromised ovarian reserve. Int J Gynecol Cancer. 2014;24(2): 233-7.[Crossref] [PubMed] 
  28. Shapira M, Raanani H, Feldman B, et al. BRCA mutation carriers show normal ovarian response in in vitro fertilization cycles.Fertil Steril. 2015;104(5):1162-7.[Crossref] [PubMed] 
  29. Grynberg M, Dagher Hayeck B, Papanikolaou EG, Sifer C, Sermondade N, Sonigo C. BRCA1/2 gene mutations do not affect the capacity of oocytes from breast cancer candidates for fertility preservation to mature in vitro. Hum Reprod. 2019;34(2):374-9.[Crossref] [PubMed] 
  30. Malacarne E, Devesa M, Martinez F, Rodriguez I, Coroleu B. COH outcomes in breast cancer patients for fertility preservation: a comparison with the expected response by age. J Assist Reprod Genet. 2020;37(12): 3069-76.[Crossref] [PubMed] 
  31. Ponce J, Fernandez-Gonzalez S, Calvo I, et al. Assessment of ovarian reserve and reproductive outcomes in BRCA1 or BRCA2 mutation carriers. Int J Gynecol Cancer. 2020;30(1):83-8.[Crossref] [PubMed] 
  32. Hu KL, Wang S, Ye X, Zhang D. Effects of BRCA gene mutation on female reproductive potential: A systematic review. Maturitas. 2020;137:11-17.[Crossref] [PubMed] 
  33. Oktay KH, Bedoschi G, Goldfarb SB, et al. Increased chemotherapy-induced ovarian reserve loss in women with germline BRCA mutations due to oocyte deoxyribonucleic acid double strand break repair deficiency. Fertil Steril. 2020;113(6):1251-60.[Crossref] [PubMed] 
  34. Peccatori FA, Mangili G, Bergamini A, et al. Fertility preservation in women harboring deleterious BRCA mutations: ready for prime time? Hum Reprod. 2018;33(2):181-7.[Crossref] [PubMed] 
  35. Lin W, Titus S, Moy F, Ginsburg ES, Oktay K. Ovarian Aging in Women With BRCA Germline Mutations. J Clin Endocrinol Metab. 2017;102(10):3839-3847.[Crossref] [PubMed] [PMC] 
  36. Turan V, Oktay K. BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging. Hum Reprod Update. 2020;26(1):43-57.[Crossref] [PubMed] [PMC]