遗传性卵巢癌的筛查与预防研究进展

Research progress in screening and prevention of hereditary ovarian cancer

摘要

卵巢癌是女性生殖系统的常见恶性肿瘤之一，因早期症状隐匿，超过70%的患者在确诊时已是晚期，此时的5年生存率不足40%。约有15%的卵巢癌与遗传性基因突变相关，又以BRCA1/2基因突变最为常见。通过系统的风险评估、遗传咨询及基因检测可识别遗传性卵巢癌的高危人群，并采取进一步筛查与预防措施。目前，卵巢癌筛查以经阴道超声联合血清CA-125检测为主要手段，但其敏感性和特异性有限；卵巢癌预防以双侧输卵管卵巢切除术最为有效，但手术后遗症严重。未来需进一步完善遗传性卵巢癌高危人群的早期识别体系，同时开发高特异性生物标志物，并探索更个体化的手术时机。

Abstract

Ovarian cancer is one of the common malignant tumours of the female reproductive system. As early symptoms are often subtle, over 70% of patients are diagnosed at an advanced stage, at which point the five-year survival rate is less than 40%. Approximately 15% of ovarian cancers are associated with hereditary gene mutations, with BRCA1/2 mutations being the most common. Through systematic risk assessment, genetic counselling, and genetic testing, high-risk populations for hereditary ovarian cancer can be identified, and further screening and preventive measures can be implemented. Currently, ovarian cancer screening primarily relies on transvaginal ultrasound combined with serum CA-125 testing. However, the sensitivity and specificity of these methods are limited. Bilateral salpingo-oophorectomy is the most effective method of ovarian cancer prevention, but it is associated with significant postoperative sequelae. In the future, it will be necessary to further refine the early identification system for high-risk populations for hereditary ovarian cancer, whilst developing highly specific biomarkers and exploring more personalized timing of surgery.

关键词

遗传性卵巢癌 / BRCA1/2 / 筛查 / 预防

Key words

Hereditary ovarian cancer / BRCA1/2 / Screening / Prevention

参考文献

[1] RODRIGUEZ I V, GHEZELAYAGH T, PENNINGTON K P, et al. Prevention of ovarian cancer: Where are we now and where are we going?[J]. Curr Oncol Rep, 2024, 26(11): 1355-1366.

[2] 中国抗癌协会家族遗传性肿瘤专业委员会. 中国家族遗传性肿瘤临床诊疗专家共识(2021年版)(2)——家族遗传性卵巢癌[J]. 中国肿瘤临床, 2021, 48(24): 1243-1247.

[3] KAUSAR M A, ALSHAMMARI K F, ALENAZI F, et al. RAD51 and PALB2 in precision oncology: Clinical implications for HRD associated breast and ovarian cancers (review)[J]. Int J Oncol, 2025, 67(2): 65.

[4] GOLDFELD E I, KELLY B E, RING K L. What about the others? Clinical management of gynecologic cancer risk in patients with moderate-risk hereditary cancer genes (ATM, BRIP1, RAD51C, RAD51D, and PALB2)[J]. Clin Obstet Gynecol, 2024, 67(4): 696-701.

[5] QIN Z, KUOK C N, DONG H, et al. Can population BRCA screening be applied in non-Ashkenazi Jewish populations? Experience in Macau population[J]. J Med Genet, 2021, 58(9): 587-591.

[6] STRUEWING J P, HARTGE P, WACHOLDER S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews[J]. N Engl J Med, 1997, 336(20): 1401-1408.

[7] US PREVENTIVE SERVICES TASK FORCE, OWENS D K, DAVIDSON K W, et al. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US preventive services task force recommendation statement[J]. JAMA, 2019, 322(7): 652-665.

[8] KEKEEVA T, DUDINA I, ANDREEVA Y, et al. Molecular subgroups of HRD positive ovarian cancer and their prognostic significance[J]. Int J Mol Sci, 2024, 25(24): 13549.

[9] CERRETELLI G, AGER A, ARENDS M J, et al. Molecular pathology of Lynch syndrome[J]. J Pathol, 2020, 250(5): 518-531.

[10] RAN X, JING H, LI Z. The clinical features and management of Lynch syndrome-associated ovarian cancer[J]. J Obstet Gynaecol Res, 2022, 48(7): 1538-1545.

[11] MOLDOVAN R, KEATING S, CLANCY T. The impact of risk-reducing gynaecological surgery in premenopausal women at high risk of endometrial and ovarian cancer due to Lynch syndrome[J]. Fam Cancer, 2015, 14(1): 51-60.

[12] GHOSE A, BOLINA A, MAHAJAN I, et al. Hereditary ovarian cancer: Towards a cost-effective prevention strategy[J]. Int J Environ Res Public Health, 2022, 19(19): 12057.

[13] RYAN N A J, EVANS D G, GREEN K, et al. Pathological features and clinical behavior of Lynch syndrome-associated ovarian cancer[J]. Gynecol Oncol, 2017, 144(3): 491-495.

[14] YU J, DING P R, JIANG W. Screening and management of Lynch syndrome: The Chinese experience[J]. Clin Colon Rectal Surg, 2023, 36(6): 369-377.

[15] TACHECI I, KOPACOVA M, BURES J. Peutz-Jeghers syndrome[J]. Curr Opin Gastroenterol, 2021, 37(3): 245-254.

[16] PIETRAGALLA A, ARCIERI M, MARCHETTI C, et al. Ovarian cancer predisposition beyond BRCA1 and BRCA2 genes[J]. Int J Gynecol Cancer, 2020, 30(11): 1803-1810.

[17] DALY M B, PILARSKI R, YURGELUN M B, et al. NCCN guidelines insights: Genetic/familial high-risk assessment: Breast, ovarian, and pancreatic, version 1.2020[J]. J Natl Compr Canc Netw, 2020, 18(4): 380-391.

[18] US PREVENTIVE SERVICES TASK FORCE, GROSSMAN D C, CURRY S J, et al. Screening for ovarian cancer: US preventive services task force recommendation statement[J]. JAMA, 2018, 319(6): 588-594.

[19] BELLCROSS C A. Hereditary breast and ovarian cancer: An updated primer for OB/GYNs[J]. Obstet Gynecol Clin North Am, 2022, 49(1): 117-147.

[20] US PREVENTIVE SERVICES TASK FORCE. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: Recommendation statement[J]. Am Fam Physician, 2015, 91(2): Online.

[21] MARMOLEJO D H, WONG M Y Z, BAJALICA-LAGERCRANTZ S, et al. Overview of hereditary breast and ovarian cancer (HBOC) guidelines across Europe[J]. Eur J Med Genet, 2021, 64(12): 104350.

[22] MCDEVITT T, DURKIE M, ARNOLD N, et al. EMQN best practice guidelines for genetic testing in hereditary breast and ovarian cancer[J]. Eur J Hum Genet, 2024, 32(5): 479-488.

[23] CHEN L M, MODESITT S. Hereditary cancer syndromes and risk assessment: Acog committee opinion, number 793[J]. Obstet Gynecol, 2019, 134(6): e143-e149.

[24] MCALARNEN L, STEARNS K, UYAR D. Challenges of genomic testing for hereditary breast and ovarian cancers[J]. Appl Clin Genet, 2021, 14: 1-9.

[25] PALUCH-SHIMON S, CARDOSO F, SESSA C, et al. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening[J]. Ann Oncol, 2016, 27(suppl 5): v103-v110.

[26] FANALE D, PIVETTI A, CANCELLIERE D, et al. BRCA1/2 variants of unknown significance in hereditary breast and ovarian cancer (HBOC) syndrome: Looking for the hidden meaning[J]. Crit Rev Oncol Hematol, 2022, 172: 103626.

[27] 中国三级妇产科医院/妇幼保健院联盟妇科肿瘤遗传咨询协作组, 中国抗癌协会中西整合子宫内膜癌专业委员会. 妇科肿瘤遗传咨询专家共识(2023年版)[J]. 中国癌症杂志, 2023, 33(11): 1041-1064.

[28] LEI H, ZHANG M, ZHANG L, et al. Overview on population screening for carriers with germline BRCA mutation in China[J]. Front Oncol, 2022, 12: 1002360.

[29] 郭洁, 刘彦军, 申建芬. 邯郸地区卵巢癌患者直系亲属接受遗传咨询及基因检测意愿的调查[J]. 实用预防医学, 2023, 30(4): 464-469.

[30] 上海市医疗保障局. 关于公布本市部分新增医疗服务项目价格和可另收费一次性使用医疗器械目录的通知[EB/OL]. (2020-11-09)[2026-04-14]. https://ybj.sh.gov.cn/gsgg/20201109/296b2dbc699f495e9927ded43a8b6786.html.

[31] 福建省医疗保障局. 福建省医疗保障局关于优化脱氧核糖核酸(DNA)测序等项目价格有关问题的通知(闽医保〔2022〕119号)[EB/OL]. (2022-11-28)[2026-04-14]. https://ybj.fujian.gov.cn/zfxxgkzl/fdzdgknr/zcwj/202211/t20221128_6063594.htm.

[32] 国家医疗保障局, 人力资源社会保障部. 国家基本医疗保险、工伤保险和生育保险药品目录(2025年)[S/OL]. (2025-12-07)[2026-04-14]. https://www.nhsa.gov.cn/art/2025/12/7/art_104_18970.html.

[33] 王辉, 王霞, 郜意, 等 . 遗传性乳腺癌-卵巢癌综合征患者一级亲属接受基因筛查的现状及影响因素研究[J]. 中国癌症杂志, 2023, 33(5): 499-505.

[34] JACOBS I J, MENON U, RYAN A, et al. Ovarian cancer screening and mortality in the UK collaborative trial of ovarian cancer screening (UKCTOCS): A randomised controlled trial[J]. Lancet, 2016, 387(10022): 945-956.

[35] SESSA C, BALMAÑA J, BOBER S L, et al. Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO Clinical Practice Guideline[J]. Ann Oncol, 2023, 34(1): 33-47.

[36] VAN NAGELL J R, MILLER R W, DESIMONE C P, et al. Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening[J]. Obstet Gynecol, 2011, 118(6): 1212-1221.

[37] ZHU Q. A review of co-registered transvaginal photoacoustic and ultrasound imaging for ovarian cancer diagnosis[J]. Curr Opin Biomed Eng, 2022, 22: 100381.

[38] ZHANG M, CHENG S, JIN Y, et al. Roles of CA125 in diagnosis, prediction, and oncogenesis of ovarian cancer[J]. Biochim Biophys Acta Rev Cancer, 2021, 1875(2): 188503.

[39] GU Z, HE Y, ZHANG Y, et al. Postprandial increase in serum CA125 as a surrogate biomarker for early diagnosis of ovarian cancer[J]. J Transl Med, 2018, 16(1): 114.

[40] ELIAS K M, FENDLER W, STAWISKI K, et al. Diagnostic potential for a serum miRNA neural network for detection of ovarian cancer[J]. eLife, 2017, 6: e28932.

[41] YOKOI A, MATSUZAKI J, YAMAMOTO Y, et al. Integrated extracellular microRNA profiling for ovarian cancer screening[J]. Nat Commun, 2018, 9(1): 4319.

[42] KANDIMALLA R, WANG W, YU F, et al. OCaMIR - A noninvasive, diagnostic signature for early stage ovarian cancer: A multi-cohort retrospective and prospective study[J]. Clin Cancer Res, 2021, 27(15): 4277-4286.

[43] ELIAS K, SMYCZYNSKA U, STAWISKI K, et al. Identification of BRCA1/2 mutation female carriers using circulating microRNA profiles[J]. Nat Commun, 2023, 14(1): 3350.

[44] FRIEBEL T M, DOMCHEK S M, REBBECK T R. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: Systematic review and meta-analysis[J]. J Natl Cancer Inst, 2014, 106(6): dju091.

[45] PARK J, HUANG D, CHANG Y J, et al. Oral contraceptives and risk of breast cancer and ovarian cancer in women with a BRCA1 or BRCA2 mutation: A meta-analysis of observational studies[J]. Carcinogenesis, 2022, 43(3): 231-242.

[46] HUBER D, SEITZ S, KAST K, et al. Use of oral contraceptives in BRCA mutation carriers and risk for ovarian and breast cancer: A systematic review[J]. Arch Gynecol Obstet, 2020, 301(4): 875-884.

[47] SELLERS T A, PERES L C, HATHAWAY C A, et al. Prevention of epithelial ovarian cancer[J]. Cold Spring Harb Perspect Med, 2023, 13(8): a038216.

[48] NELSON H D, FU R, ZAKHER B, et al. Medication use for the risk reduction of primary breast cancer in women: Updated evidence report and systematic review for the US preventive services task force[J]. JAMA, 2019, 322(9): 868-886.

[49] VAN BOMMEL M H D, INTHOUT J, VELDMATE G, et al. Contraceptives and cancer risks in BRCA1/2 pathogenic variant carriers: A systematic review and meta-analysis[J]. Hum Reprod Update, 2023, 29(2): 197-217.

[50] BARNARD M E, POOLE E M, CURHAN G C, et al. Association of analgesic use with risk of ovarian cancer in the nurses' health studies[J]. JAMA Oncol, 2018, 4(12): 1675-1682.

[51] CHERIF S, AMINE A, THIES S, et al. Prevalence of human papillomavirus detection in ovarian cancer: A meta-analysis[J]. Eur J Clin Microbiol Infect Dis, 2021, 40(9): 1791-1802.

[52] PARADOWSKA E, HAREZ·A D A, KANIA K D, et al. Human papillomavirus infection of the fallopian tube as a potential risk factor for epithelial ovarian cancer[J]. Sci Rep, 2024, 14(1): 21602.

[53] CAZZANIGA M, CARDINALI M, DI PIERRO F, et al. Ovarian microbiota, ovarian cancer and the underestimated role of HPV[J]. Int J Mol Sci, 2022, 23(24): 16019.

[54] XU H, DING Y, XIN X, et al. Dietary fiber intake is associated with a reduced risk of ovarian cancer: A dose-response meta-analysis[J]. Nutr Res, 2018, 57: 1-11.

[55] CHRISTAKOUDI S, PAGONI P, FERRARI P, et al. Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort[J]. Int J Cancer, 2021, 148(7): 1637-1651.

[56] EL-SHERIF A, EL-SHERIF S, TAYLOR A H, et al. Ovarian cancer: Lifestyle, diet and nutrition[J]. Nutr Cancer, 2021, 73(7): 1092-1107.

[57] DOMCHEK S M, FRIEBEL T M, SINGER C F, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality[J]. JAMA, 2010, 304(9): 967-975.

[58] FINCH A P M, LUBINSKI J, MOLLER P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation[J]. J Clin Oncol, 2014, 32(15): 1547-1553.

[59] REBBECK T R, KAUFF N D, DOMCHEK S M. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers[J]. J Natl Cancer Inst, 2009, 101(2): 80-87.

[60] VUKOVIÓC P, PECCATORI F A, MASSAROTTI C, et al. Preimplantation genetic testing for carriers of BRCA1/2 pathogenic variants[J]. Crit Rev Oncol Hematol, 2021, 157: 103201.

[61] KENKHUIS M J, DE BOCK G H, ELFERINK P O, et al. Short-term surgical outcome and safety of risk reducing salpingo-oophorectomy in BRCA1/2 mutation carriers[J]. Maturitas, 2010, 66(3): 310-314.

[62] GABA F, ROBBANI S, SINGH N, et al. Preventing ovarian cancer through early excision of tubes and late ovarian removal (protector): Protocol for a prospective non-randomised multi-center trial[J]. Int J Gynecol Cancer, 2021, 31(2): 286-291.

[63] STEENBEEK M P, HARMSEN M G, HOOGERBRUGGE N, et al. Association of salpingectomy with delayed oophorectomy versus salpingo-oophorectomy with quality of life in BRCA1/2 pathogenic variant carriers: A nonrandomized controlled trial[J]. JAMA Oncol, 2021, 7(8): 1203-1212.

[64] KITSON S J, BAFLIGIL C, RYAN N A J, et al. BRCA1 and BRCA2 pathogenic variant carriers and endometrial cancer risk: A cohort study[J]. Eur J Cancer, 2020, 136: 169-175.

[65] SHU C A, PIKE M C, JOTWANI A R, et al. Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations[J]. JAMA Oncol, 2016, 2(11): 1434-1440.

基金资助

国家重点研发计划“政府间国际科技创新合作”重点专项项目(2019YFE0198800)

浙江省万人计划科技创新领军人才项目(2021R52020)