BRCA基因突变女性携带者生育力保存研究进展

doi:10.12280/gjfckx.20200287

摘要/Abstract

摘要：

长期以来,乳腺癌易感基因1（BRCA1）和BRCA2突变被认为是乳腺癌及卵巢癌的独立危险因素。针对肿瘤的任何治疗方式（如双侧输卵管切除术等）都不可避免地对患者生育力带来破坏或丢失。随着女性生育年龄的普遍推迟和癌症发病年龄的年轻化,生育力保护已成为肿瘤治疗决策时经常需要面临的问题。同时,一些研究表明BRCA基因突变也可导致卵巢功能障碍,尤其是卵巢储备能力的下降。就BRCA1/2基因突变携带者可能面临的生育力问题及目前已有的保存生育力技术进行综述为临床提供参考。

关键词: 基因,BRCA1, 基因,BRCA2, 突变, 生育力, 卵巢储备功能, 生殖技术,辅助

Abstract:

Deleterious mutations in BRCA1 or BRCA2 genes have long been recognized as independent risk factors, mostly for breast and ovarian cancer. Any treatment for the turmor, such as bilateral salpingectomy, inevitably results in damage or loss of fertility. With the general postponement of women′s childbearing age and the younger age of cancer onset, fertility perservation has become a problem that often needs to be faced when making tumor treatment decisions. At the same time, some research evidence suggests that this genetic state may also be associated with ovarian dysfunction, especially the reduction of ovarian reserve. In this paper, we reviewed the fertility problems that BRCA1/2 gene mutation carriers may face and the existing fertility preservation techniques.

Key words: Genes,BRCA1, Genes,BRCA2, Mutation, Fertility, Ovarian reserve, Reproductive techniques,assisted

刘晓时, 狄文. BRCA基因突变女性携带者生育力保存研究进展[J]. 国际妇产科学杂志, 2021, 48(1): 71-74.

LIU Xiao-shi, DI Wen. Advances in Fertility Preservation in Women with BRCA Mutations[J]. Journal of International Obstetrics and Gynecology, 2021, 48(1): 71-74.

图/表 1

参考文献 27

[1]	Howlader N, Noone AM, Krapcho MJ, et al. SEER Cancer Statistics Review,1975-2010[M]. Bethesda: National Cancer Institute, 2013: 1-15.
[2]	Antoniou AC, Gayther SA, Stratton JF, et al. Risk models for familial ovarian and breast cancer[J]. Genet Epidemiol, 2000,18(2):173-190. doi: 10.1002/(SICI)1098-2272(200002)18:2<173::AID-GEPI6>3.0.CO;2-R. doi: 10.1002/(SICI)1098-2272(200002)18:2<173::AID-GEPI6>3.0.CO;2-R pmid: 10642429
[3]	Schmidt MK, van den Broek AJ, Tollenaar RA, et al. Breast Cancer Survival of BRCA1/BRCA2 Mutation Carriers in a Hospital-Based Cohort of Young Women[J]. J Natl Cancer Inst, 2017,109(8):10. doi: 10.1093/jnci/djw329.
[4]	Turan V, Oktay K. BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging[J]. Hum Reprod Update, 2020,26(1):43-57. doi: 10.1093/humupd/dmz043. doi: 10.1093/humupd/dmz043 pmid: 31822904
[5]	Lin W, Titus S, Moy F, et al. Ovarian Aging in Women With BRCA Germline Mutations[J]. J Clin Endocrinol Metab, 2017,102(10):3839-3847. doi: 10.1210/jc.2017-00765. doi: 10.1210/jc.2017-00765 pmid: 28938488
[6]	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]. J Assist Reprod Genet, 2020,37(3):709-715. doi: 10.1007/s10815-019-01658-9. doi: 10.1007/s10815-019-01658-9 pmid: 31872386
[7]	Macedo GS, Alemar B, Ashton-Prolla P. Reviewing the characteristics of BRCA and PALB2-related cancers in the precision medicine era[J]. Genet Mol Biol, 2019,42(1 suppl 1):215-231. doi: 10.1590/1678-4685-GMB-2018-0104. doi: 10.1590/1678-4685-GMB-2018-0104 pmid: 31067289
[8]	Liu Y, Lu LY. BRCA1 and homologous recombination: implications from mouse embryonic development[J]. Cell Biosci, 2020,10:49. doi: 10.1186/s13578-020-00412-4. doi: 10.1186/s13578-020-00412-4 pmid: 32257107
[9]	Son KA, Lee DY, Choi D. Association of BRCA Mutations and Anti-müllerian Hormone Level in Young Breast Cancer Patients[J]. Front Endocrinol(Lausanne), 2019,10:235. doi: 10.3389/fendo.2019.00235.
[10]	Antoniou A, Pharoah PD, Narod S, 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[J]. Am J Hum Genet, 2003,72(5):1117-1130. doi: 10.1086/375033. doi: 10.1086/375033 pmid: 12677558
[11]	Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers[J]. JAMA, 2017,317(23):2402-2416. doi: 10.1001/jama.2017.7112. doi: 10.1001/jama.2017.7112 pmid: 28632866
[12]	Wallace WH, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte[J]. Hum Reprod, 2003,18(1):117-121. doi: 10.1093/humrep/deg016. doi: 10.1093/humrep/deg016 pmid: 12525451
[13]	Taylan E, Oktay KH. Current state and controversies in fertility preservation in women with breast cancer[J]. World J Clin Oncol, 2017,8(3):241-248. doi: 10.5306/wjco.v8.i3.241. doi: 10.5306/wjco.v8.i3.241 pmid: 28638793
[14]	Kalich-Philosoph L, Roness H, Carmely A, et al. Cyclophosphamide triggers follicle activation and "burnout"; AS101 prevents follicle loss and preserves fertility[J]. Sci Transl Med, 2013, 5(185):185ra62. doi: 10.1126/scitranslmed.3005402. doi: 10.1126/scitranslmed.3005624 pmid: 23677590
[15]	Kim SY, Cho GJ, Davis JS. Consequences of chemotherapeutic agents on primordial follicles and future clinical applications[J]. Obstet Gynecol Sci, 2019,62(6):382-390. doi: 10.5468/ogs.2019.62.6.382. doi: 10.5468/ogs.2019.62.6.382 pmid: 31777733
[16]	李微, 张娜. 女性生育力保存技术的研究进展[J]. 国际生殖健康/计划生育杂志, 2016,35(5):409-412. doi: 10.3969/j.issn.1674-1889.2006.05.013.
[17]	王生存, 李碧春. 冷冻卵巢移植研究进展[J]. 国际生殖健康/计划生育杂志, 2019,38(6):498-503. doi: 10.3969/j.issn.1674-1889.2009.06.014.
[18]	Pacheco F, Oktay K. Current Success and Efficiency of Autologous Ovarian Transplantation: A Meta-Analysis[J]. Reprod Sci, 2017,24(8):1111-1120. doi: 10.1177/1933719117702251. doi: 10.1177/1933719117702251 pmid: 28701069
[19]	张伟伟, 杨琨, 张云山. 社会性卵子冷冻保存的伦理思考[J]. 国际生殖健康/计划生育杂志, 2017,36(5):400-403. doi: 10.3969/j.issn.1674-1889.2017.05.013.
[20]	Bastings L, Beerendonk CC, Westphal JR, et al. Autotransplantation of cryopreserved ovarian tissue in cancer survivors and the risk of reintroducing malignancy: a systematic review[J]. Hum Reprod Update, 2013,19(5):483-506. doi: 10.1093/humupd/dmt020. doi: 10.1093/humupd/dmt020
[21]	Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. In vitro maturation: a committee opinion[J]. Fertil Steril, 2013,99(3):663-666. doi: 10.1016/j.fertnstert.2012.12.031. doi: 10.1016/j.fertnstert.2012.12.031
[22]	Hoekman EJ, Broeders E, Louwe LA, et al. Ovarian function after ovarian transposition and additional pelvic radiotherapy: A systematic review[J]. Eur J Surg Oncol, 2019,45(8):1328-1340. doi: 10.1016/j.ejso.2019.02.017. doi: 10.1016/j.ejso.2019.02.017 pmid: 30857878
[23]	Horicks F, Van Den Steen G, Gervy C, et al. Both in vivo FSH depletion and follicular exposure to Gonadotrophin-releasing hormone analogues in vitro are not effective to prevent follicular depletion during chemotherapy in mice[J]. Mol Hum Reprod, 2018,24(4):221-232. doi: 10.1093/molehr/gay005. doi: 10.1093/molehr/gay005 pmid: 29438534
[24]	Oribamise EI, Ashiru OA, Iloabachie EC, et al. Preimplantation Genetic Testing for Breast Cancer[J]. Niger Med J, 2019,60(3):99-105. doi: 10.4103/nmj.NMJ_124_18. pmid: 31543559
[25]	Derks-Smeets IA, de Die-Smulders CE, Mackens S, et al. Hereditary breast and ovarian cancer and reproduction: an observational study on the suitability of preimplantation genetic diagnosis for both asymptomatic carriers and breast cancer survivors[J]. Breast Cancer Res Treat, 2014,145(3):673-681. doi: 10.1007/s10549-014-2951-5. doi: 10.1007/s10549-014-2951-5 pmid: 24748567
[26]	Chiti MC, Dolmans MM, Donnez J, et al. Fibrin in Reproductive Tissue Engineering: A Review on Its Application as a Biomaterial for Fertility Preservation[J]. Ann Biomed Eng, 2017,45(7):1650-1663. doi: 10.1007/s10439-017-1817-5. doi: 10.1007/s10439-017-1817-5 pmid: 28271306
[27]	Kim J, Turan V, Oktay K. Long-Term Safety of Letrozole and Gonadotropin Stimulation for Fertility Preservation in Women With Breast Cancer[J]. J Clin Endocrinol Metab, 2016,101(4):1364-1371. doi: 10.1210/jc.2015-3878. doi: 10.1210/jc.2015-3878 pmid: 26751194

化疗药物	类别	作用机制	药物作用的细胞周期	不孕风险
5-氟尿嘧啶	抗代谢药物	与四氢叶酸及胸苷酸合成酶（TS）共价结合使其失活,从而阻止DNA复制	S期	低风险
甲氨蝶呤	抗代谢药物	与叶酸竞争性抑制二氢叶酸还原酶,使DNA合成受阻	S期	低风险
博来霉素	蒽环类药物	通过形成毒性氧自由基导致DNA断裂	S期	低风险
紫杉醇	紫杉烷类	有丝分裂过程中通过干扰微管的形成抑制细胞分裂	M期	低风险
更生霉素	抗肿瘤抗生素	与转录起始复合物结合抑制mRNA转录	细胞周期非特异性	中低风险
顺铂	铂类化合物	共价结合DNA双链形成交联,使DNA在复制过程中断裂	细胞周期特异性	中等风险
环磷酰胺	烷基化剂	共价结合DNA双链形成交联,使DNA在复制过程中断裂	细胞周期非特异性	高风险

化疗药物	类别	作用机制	药物作用的细胞周期	不孕风险
5-氟尿嘧啶	抗代谢药物	与四氢叶酸及胸苷酸合成酶（TS）共价结合使其失活,从而阻止DNA复制	S期	低风险
甲氨蝶呤	抗代谢药物	与叶酸竞争性抑制二氢叶酸还原酶,使DNA合成受阻	S期	低风险
博来霉素	蒽环类药物	通过形成毒性氧自由基导致DNA断裂	S期	低风险
紫杉醇	紫杉烷类	有丝分裂过程中通过干扰微管的形成抑制细胞分裂	M期	低风险
更生霉素	抗肿瘤抗生素	与转录起始复合物结合抑制mRNA转录	细胞周期非特异性	中低风险
顺铂	铂类化合物	共价结合DNA双链形成交联,使DNA在复制过程中断裂	细胞周期特异性	中等风险
环磷酰胺	烷基化剂	共价结合DNA双链形成交联,使DNA在复制过程中断裂	细胞周期非特异性	高风险