BACKGROUND & AIMS: Whether the intake of docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, is beneficial for ovarian cancer (OC) remains controversial and we hope to disentangle this puzzle using genetic data from large-scale populations in European and Asian. METHODS: We employed, for the first time, a systematic Mendelian randomization (MR) design to comprehensively evaluate the causal effect of plasma DHA levels, an objective biomarker of DHA intake, on OC risk in European and then verified the extrapolation of the results in the Asian. Data in the analysis included genetic association data obtained from large-scale genome-wide association studies with 13,499 individuals for plasma DHA measurements and 66,450 individuals for OC in the European population, and 1361 individuals for plasma DHA measurements and 61,457 individuals for OC in the Asian population. The causal relationship between DHA and OC was estimated using the inverse-variance weighted approach, together with extensive validation and sensitivity analyses to verify the main results. RESULTS: In the European population, MR evidence suggested a causal relationship between higher plasma DHA levels and lower OC risk (OR, 0.89 for OC per one-SD increment in DHA; 95% CI, 0.83 to 0.96; P = 0.003). Subgroup analysis by histological type of OC indicated that this observed association was stronger among endometrioid ovarian cancer (EOC) (OR, 0.82; 95% CI, 0.69 to 0.96; P = 0.014). A similar causal association of borderline significance was reached in the Asian replication set. The above results were consistently supported by a series of validation and sensitivity analyses. CONCLUSION: Our study provided robust genetic evidence for a protective association between plasma DHA levels and lower risk of OC, especially EOC, in the European population. These findings may inform prevention strategies and interventions directed towards DHA intake and OC.
- Klíčová slova
- Docosahexaenoic acid (DHA), Genome-wide association study (GWAS), Mendelian randomization (MR), Ovarian cancer, n-3 polyunsaturated fatty acid (PUFA),
- MeSH
- celogenomová asociační studie MeSH
- jednonukleotidový polymorfismus genetika MeSH
- kyseliny dokosahexaenové MeSH
- lidé MeSH
- mendelovská randomizace MeSH
- nádory vaječníků * epidemiologie genetika prevence a kontrola MeSH
- omega-3 mastné kyseliny * MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- kyseliny dokosahexaenové MeSH
- omega-3 mastné kyseliny * MeSH
BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.
- Klíčová slova
- BRCA1, BRCA2, epidemiology, multivariate, observational, oral contraceptives, ovarian cancer, retrospective, risk, survival bias,
- MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- kohortové studie MeSH
- kontraceptiva orální aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace * MeSH
- nádory vaječníků epidemiologie genetika prevence a kontrola MeSH
- následné studie MeSH
- proporcionální rizikové modely MeSH
- protein BRCA1 genetika MeSH
- protein BRCA2 genetika MeSH
- retrospektivní studie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa epidemiologie MeSH
- Názvy látek
- BRCA1 protein, human MeSH Prohlížeč
- BRCA2 protein, human MeSH Prohlížeč
- kontraceptiva orální MeSH
- protein BRCA1 MeSH
- protein BRCA2 MeSH
INTRODUCTION: An ovarian cancer prevention program must encourage the application of factors associated with decreased risk that include both surgical and non-surgical approaches. Non-surgical preventive approaches include oral contraceptives, parity, multiparity and breastfeeding. In addition, approaches that decrease inflammation and oxidative stress such as regular exercise and a healthy diet are also important. Surgical approaches include tubal ligation, hysterectomy and prophylactic bilateral salpingo-oophorectomy. OBJECTIVE: To highlight protective approaches for the prevention of ovarian cancer in order to increase awareness among women of the general population and too find out whether or not these approaches are enough to prevent the disease. DESIGN: Review article. SETTING: Department of Chemical Pathology, NHLS, Tygerberg Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. METHODS: Literary sources related to the topic were used. Articles were selected primarily based on PubMed and Google searches. CONCLUSION: Ovarian cancer cannot be prevented completely, however the application of preventive approaches may decrease the risk significantly. Although, multiparity followed by long periods of breastfeeding may not seem feasible for most today women, it is the most pronounced preventive approach for women in the general population. Tubal ligation, hysterectomy also reduce the risk significantly. Opportunistic salpingectomy may provide better prevention for women at average risk, while women at high risk (BRCA mutation and family with history of ovarian cancer) are advised to undergo risk-reducing salpingo-oophorectomy. Highlighting these approaches may increase women's awareness towards decreasing risk and decrease the incidence of ovarian cancer and potentially increase the five-year survival rate.
- Klíčová slova
- Aspirin, breastfeeding, contraceptives, ovarian cancer, parity, physical activity, prophylactic surgeries,
- MeSH
- epiteliální ovariální karcinom prevence a kontrola MeSH
- lidé MeSH
- nádory vaječníků prevence a kontrola MeSH
- ovarektomie * MeSH
- profylaktické chirurgické výkony metody MeSH
- salpingektomie MeSH
- salpingo-ooforektomie * MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
An inherited predisposition to breast cancer underlies 5-10% of breast tumors. High-risk BRCA1 and BRCA2 genes result in an 85% lifetime risk of breast cancer and a 20-60% lifetime risk of ovarian cancer. Next-generation sequencing or massive parallel sequencing are now established testing methods that enable screening for many genes that predispose to heterogeneous hereditary cancer syndromes (22 genes are required by the health insurance companies). In addition to BRCA1 and BRCA2, inherited mutations in other genes predispose to breast and/or ovarian cancer. High-risk breast cancer genes include TP53, STK11, CDH1, PTEN, PALB2, and NF1, while moderate-risk (2-4 times increased risk) breast cancer genes include ATM, CHEK2, and NBN. Moderate risk is also suggested for Lynch syndrome, MUTYH, BRIP1, RAD51C, RAD51D, BARD1, FANCA, FANCC, FANCM, BLM, WRN genes. In heterozygotes for other recessive syndromes the risk of developing breast cancer is subject to current research. Low-risk genes are (mostly) irrelevant from a clinical perspective. Other genes that increase the risk of ovarian cancer include the genes for Lynch syndrome, the BRIP1, RAD51C and RAD51D genes. Preventive care should be proposed based on assumed cumulative breast cancer risk (see http: //www.mamo.cz): a risk of >20% for BRCA1/2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, and NF1; and a risk of 10-20% for BRIP1, RAD51C, RAD51B, BARD1, FANCA, FANCC, FANCM, NBN, BLM, and WRN. The genetic risk should be assessed by a geneticist and be based on inherited mutations and empirical risk according to family history. Prophylactic mastectomy is considered for high-risk gene carriers but not for moderate-risk gene carriers; however, it may be considered if there is an underlying family history, a risk of parenchyma of the mammary gland, or other risk factors. Ovarian cancer risk increases significantly in carriers of the BRIP1, RAD51C, and RAD51D genes. For prevention of ovarian cancer, prophylactic salpingo-oophorectomy is an important component of preventive care. In ovarian cancer families with no identified risk germline mutation, preventive salpingo-oophorectomy is not routinely recommended but may be considered as the only efficient method of prevention due to the increased empirical risk (4 times) of ovarian cancer in first-degree relatives. Supported by the grant project MH CZ - RVO (MMCI, 00209805), AZV 15-27695A and AZV 16-29959A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 17. 5. 2019 Accepted: 31. 5. 2019.
- Klíčová slova
- BRCA1, BRCA2, genes, genetic testing, high-throughput nucleotide sequencing, prophylactic mastectomy, salpingo-oophorectomy,
- MeSH
- genetická predispozice k nemoci * MeSH
- lidé MeSH
- nádory prsu genetika prevence a kontrola MeSH
- nádory vaječníků genetika prevence a kontrola MeSH
- profylaktická mastektomie MeSH
- rizikové faktory MeSH
- salpingo-ooforektomie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
This paper summarizes the current knowledge of gynecological care aspects in women with inherited predisposition to breast and ovarian cancer, i.e. BRCA1 and BRCA2 mutation carriers, and proposes guidelines for furher management of these women, addressing follow-up recommendations, prophylactic surgery indications and preimplantation genetic conseling. It evaluates cancer risk and severity of ovarian cancer in particular with regards to its high mortality resulting from aggressive biological behavior of the tumor and late detection rates. BRCA-positive women should be enrolled in prevention programs including carefull surveillance, prophylactic surgery or pre-implantation genetic counseling. Follow-up care consists of gynecological examination, expert oncogynecological ultrasound and tumor marker CA125 examination every six months. However, the most effective strategy for mortality reduction in ovarian cancer is prophylactic surgery--salpingo-oophorectomy (and hysterectomy). The optimal age for surgery is between 35 to 40 years. Prophylactic salpingo-oophorectomy performed in premenopausal women was proved to reduce the risk of ovarian as well as breast cancer. Symptoms of estrogen deficiency after prophylactic surgery can be suppressed by administration of hormone replacement therapy without increasing the risk of breast cancer. Preimplantation genetic diagnosis is an effective way to prevent the trans--mission of hereditary predisposition to the next generation. The management of patients with hereditary suspceptibility to ovarian cancer should be confined to specialized centres.
BACKGROUND: The reduction of ovarian cancer (OC) risk in women with a history of tubal ligation (TL) has been reported repeatedly, mostly on small populations. We have aimed to provide a critical overview of the studies available to date and to conduct a meta-analysis. METHODS: There were 40 relevant studies identified. The studies were divided into two groups for strict and extended meta-analysis, respectively. Subgroup analysis was performed for age, time dependency since TL, histological types of OC and BReast CAncer (BRCA) mutation. RESULTS: Meta-analysis of 13 strictly selected studies showed a reduced risk of epithelial OC by 34%. The protective effect of TL was confirmed even in a subgroup of women 10-14 years after the procedure. The risk reduction was confirmed for the endometrioid (RR = 0.40) and serous (RR = 0.73) cancers but not for mucinous. CONCLUSIONS: The review of relevant articles, as well as the meta-analysis of selected studies, yields consistent data on a significant reduction of OC risk in women who had undergone TL. The results of this meta-analysis should provide an impulse for further research on the etiology of ovarian epithelial cancers, focusing particularly on the importance of retrograde transport of endometrial cells.
- MeSH
- časové faktory MeSH
- lidé MeSH
- nádory vaječníků epidemiologie genetika prevence a kontrola MeSH
- prospektivní studie MeSH
- protein BRCA1 genetika MeSH
- protein BRCA2 genetika MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- tubární sterilizace * MeSH
- věkové faktory MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- BRCA1 protein, human MeSH Prohlížeč
- BRCA2 protein, human MeSH Prohlížeč
- protein BRCA1 MeSH
- protein BRCA2 MeSH
A recently published meta-analysis of 21 studies confirmed a protective effect of tubal ligation on the risk of invasive ovarian cancer. This protective measure has received little attention, particularly due to the elusive underlying mechanism. In this commentary we discuss available data concerning the contribution of different potential mechanisms by which tubal ligation might prevent ovarian cancer. Included were studies published in English, identified through a literature search using PubMed and EMBASE. Four main mechanisms are discussed: (a) a screening effect, (b) alteration of ovarian function, (c) a mechanical barrier against ascending carcinogenic agents and (d) prevention of endometrial and proximal Fallopian tube cell ascent. There are arguments supporting the major role of a mechanical barrier to the ascent of endometrial cells into the peritoneal cavity for decreasing risk of ovarian cancer after tubal ligation. Prevention of retrograde transport of carcinogenic substances from the vagina may be an additional mechanism.
- MeSH
- časové faktory MeSH
- chování snižující riziko * MeSH
- karcinogeny MeSH
- kinetika MeSH
- lidé MeSH
- mechanické jevy MeSH
- nádory vaječníků krevní zásobení epidemiologie prevence a kontrola MeSH
- ovarium krevní zásobení fyziologie MeSH
- plošný screening MeSH
- pohyb buněk MeSH
- primární prevence metody MeSH
- tubární sterilizace * MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- karcinogeny MeSH
The oral anti-tumor activity of a novel platinum(IV) complex, coded as LA-12, with a bulky adamantylamine ligand was evaluated and compared with another platinum(IV) complex satraplatin. The human carcinoma xenografts of colon HCT116, prostate PC3, and ovarian A2780 and A2780/cisR (resistant to cisplatin) were used to evaluate the in-vivo anti-tumor activity. The daily x 5 repeated dose regimen in equimolar doses of LA-12 and satraplatin, administered in 2 cycles, was selected for this evaluation. All doses of LA-12 and satraplatin were significantly effective in comparison with the control. The activities of LA-12 in all doses and all used tumor xenografts were higher than equimolar doses of satraplatin. The highest effect was reached with LA-12 at a dose of 60 mg/kg. The shapes of growth curves of ovarian carcinoma A2780 and its subline resistant to cisplatin after therapy with LA-12 were very similar. This shows that LA-12 is able to overcome resistance to cisplatin.
- MeSH
- amantadin analogy a deriváty terapeutické užití MeSH
- chemorezistence MeSH
- cisplatina škodlivé účinky MeSH
- ligandy MeSH
- myši nahé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory prostaty farmakoterapie patologie prevence a kontrola MeSH
- nádory tračníku farmakoterapie patologie prevence a kontrola MeSH
- nádory vaječníků farmakoterapie patologie prevence a kontrola MeSH
- organoplatinové sloučeniny terapeutické užití MeSH
- protinádorové látky terapeutické užití MeSH
- transplantace heterologní MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- amantadin MeSH
- bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
- cisplatina MeSH
- ligandy MeSH
- organoplatinové sloučeniny MeSH
- protinádorové látky MeSH
- satraplatin MeSH Prohlížeč
OBJECTIVE: Analysis of the issue of prophylactic bilateral salpingo-oophorectomy (BSO): a) during pelvic surgery for benign diagnosis; b) in women with hereditary risk of ovarian cancer. DESIGN: Review article. SETTING: Department of Obstetric and Gynecology, Charles University. METHODS: Critical review of published data. CONCLUSION: During pelvic surgery for benign diagnosis a prophylactic BSO is indicated of the age over 45, in younger women an individual approach is required, considering many aspects, including history of ovarian and breast cancer. Another indication for BSO is an increased risk of familial ovarian cancer. The surgery significantly diminished the risk of epithelial cancer of ovary, fallopian tube, and simultaneously the risk of breast cancer. There is a continuing increased risk of peritoneal cancer following the surgery. Bilateral oophorectomy together with bilateral salpingectomy is recommended. The age limit for surgery is about 35 years after careful consideration of individual risk, reproductive plans, type of mutation and age at malignant disease manifestation in previous generation. Potential alternative for women who do not accept prophylactic surgery is tubal ligation. Screening of risk group or chemoprevention by oral contraceptives are not equivalent alternatives to prophylactic surgery.
- MeSH
- genetická predispozice k nemoci MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory vaječníků genetika prevence a kontrola MeSH
- ovarektomie * MeSH
- rizikové faktory MeSH
- vejcovody chirurgie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- přehledy MeSH
OBJECTIVE: Analysis of risk and protective factors and hormone replacement therapy in the aethiology and pathogenesis of ovarian cancer. The role of hormone replacement therapy in the complex treatment in women with ovarian cancer is discussed. DESIGN: Reviewed article. SETTING: Department of Obstetrics and Gynaecology, University Hospital Ostrava. METHODS: Analysis of epidemiological studies. CONCLUSION: The role of hormone replacement therapy as a risk factor of ovarian cancer has not been confirmed. Hormone replacement therapy as a part of supportive and symptomatic therapy has been acceptable in a great deal of patients with ovarian cancer.
