Search

We multiply ascertained the BRCA1 pathogenic missense variant c.5207T > C; p.Val1736Ala (V1736A) in clinical investigation of breast and ovarian cancer families from Orkney in the Northern Isles of Scotland, UK. We sought to investigate the frequency and clinical relevance of this variant in those of Orcadian ancestry as an exemplar of the value of population cohorts in clinical care, especially in isolated populations. Oral history and birth, marriage and death registrations indicated genealogical linkage of the clinical cases to ancestors from the Isle of Westray, Orkney. Further clinical cases were identified through targeted testing for V1736A in women of Orcadian ancestry attending National Health Service (NHS) genetic clinics for breast and ovarian cancer family risk assessments. The variant segregates with female breast and ovarian cancer in clinically ascertained cases. Separately, exome sequence data from 2088 volunteer participants with three or more Orcadian grandparents, in the ORCADES research cohort, was interrogated to estimate the population prevalence of V1736A in Orcadians. The effects of the variant were assessed using Electronic Health Record (EHR) linkage. Twenty out of 2088 ORCADES research volunteers (~1%) carry V1736A, with a common haplotype around the variant. This allele frequency is ~480-fold higher than in UK Biobank participants. Cost-effectiveness of population screening for BRCA1 founder pathogenic variants has been demonstrated at a carrier frequency below the ~1% observed here. Thus we suggest that Orcadian women should be offered testing for the BRCA1 V1736A founder pathogenic variant, starting with those with known Westray ancestry.

Clinical genetics; Genetic markers; Risk factors Genética clínica; Marcadores genéticos; Factores de riesgo Genètica clínica; Marcadors genètics; Factors de risc Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Background Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. Methods Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). Results There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.

Contains fulltext : 237895.pdf (Publisher’s version ) (Open Access) 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 10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; P(trend)=.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, 0.56; 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.

Introduction: Ovarian cancer is the seventh most common and the ninth cause of death by cancer in women worldwide. In Latin America, cancer is the second cause of death and projections indicate a probable growth of the number of deaths between 2012 and 2035. Objective: To analyze the trends of incidence and mortality by ovarian cancer in Latin American countries. Method: Ecological time series study, with incidence data extracted from the International Agency for Research on Cancer, from 1990 to 2012 and mortality data from 17 countries of the World Health Organization, from 1995 to 2013. An incidence trend was analyzed by the Joinpoint regression. The average annual percentage change (AAPC) and the 95% confidence interval were calculated for incidence and mortality. Results: The highest incidence rates of ovarian cancer were observed in Cali (Colombia) and Goiânia (Brazil) in the age group older than 60 years. There was a tendency towards stability in most countries, except in Goiânia (Brazil), in the age group from 60-74 years old, with an increasing trend (AAPC: 3.4%; 95% CI: 0.3; 6.6). The highest rate of mortality by ovarian cancer occurred in Uruguay for the age group of 60-74 years and the lowest, in Belize and Guatemala, for the age group of 0-39 years. Conclusion: The incidence of ovarian cancer in Latin America has remained stable in most countries. In some, as Brazil, increase of mortality rates was observed. Introducción: el cáncer de ovario es el más común y la novena causa de muerte por cáncer en mujeres de todo el mundo. En América Latina, el cáncer es la segunda causa principal de muerte y las proyecciones se consideran un número probable de muertes entre los años 2012 y 2035. Objetivo: Analizar las tendencias de mortalidad y mortalidad por cáncer de ovario en los países latinoamericanos. Método: Estudio de series de tiempo ecológicas, con datos extraídos por la Agencia Internacional de Investigación sobre el Cáncer, de 1990 a 2012 y datos con mortalidad de 17 países de la Organización Mundial de la Salud, de 1995 a 2013. Se analizó una tendencia de incidencia mediante la regresión de Joinpoint. El cambio porcentual anual medio (AAPC) y el intervalo de confianza del 95% se calcularon para la incidencia y la mortalidad. Resultados: Las tasas de incidencia más altas de cáncer de ovario se observaron en Cali (Colombia) y Goiânia (Brasil) en el grupo de edad de más de 60 años. Hubo una tendencia hacia la estabilidad en la mayoría de los países, excepto en Goiânia (Brasil), en el grupo de edad de 60-74 años, con una tendencia creciente (AAPC: 3,4%; IC 95%: 0,3; 6,6). Las tasas de mortalidad más altas debidas al cáncer de ovario no ocurrieron en Uruguay para el grupo de edad de 60-74 años y las más bajas en Belice y Guatemala, para el grupo de edad de 0-39 años. Conclusión: La incidencia del cáncer de ovario en América Latina se ha mantenido estable en la mayoría de los países. En algunos, como Brasil, las tendencias de mortalidad pueden aumentar. Introdução: O câncer de ovário é o sétimo mais comum e a nona causa de morte por câncer em mulheres, no mundo. Na América Latina, o câncer é a segunda causa de morte, e as projeções indicam um provável crescimento no número de mortes entre os anos 2012 e 2035. Objetivo: Analisar as tendências de incidência e mortalidade para o câncer de ovário em países da América Latina. Método: Estudo ecológico de série temporal, com dados de incidência extraídos da Agência Internacional para Pesquisa do Câncer de 1990 a 2012, e dados de mortalidade obtidos de 17 países da Organização Mundial da Saúde de 1995 a 2013. A tendência de incidência foi analisada pela regressão Joinpoint. A variação percentual média anual (AAPC) e o intervalo de confiança de 95% foram calculados para incidência e mortalidade. Resultados: As maiores taxas de incidência para o câncer de ovário foram observadas em Cali (Colômbia) e Goiânia (Brasil) na faixa etária acima de 60 anos. Houve tendência de estabilidade na maioria dos países, exceto em Goiânia (Brasil), na faixa etária de 60-74 anos, que apresentou tendência de aumento (AAPC: 3,4%; IC 95%: 0,3; 6,6). A maior taxa de mortalidade por câncer de ovário ocorreu no Uruguai para a faixa etária de 60-74 anos e a menor, em Belize e Guatemala, para a faixa etária de 0-39 anos. Conclusão: A incidência do câncer de ovário na América Latina apresentou estabilidade na maioria dos países. Em alguns, como o Brasil, observou-se aumento nas tendências de mortalidade.

Purpose\ud \ud There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients.\ud \ud Methods\ud \ud Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice.\ud \ud Results\ud \ud Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer.\ud \ud Conclusion\ud \ud This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.

Objective: Histamine is suggested to play a role in ovarian carcinogenesis. We examined the association between antihistamine use and ovarian cancer risk in a nationwide case-control study. Study design: Cases (n = 5 556) comprised all women in Denmark aged 30–84 years with a histologically verified first diagnosis of epithelial ovarian cancer during 2000-2015. Age-matched population controls (n = 83 340) were selected using risk-set sampling. Data on prescription use, patient and demographic characteristics were retrieved from nationwide registries. Main outcome measures: We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for epithelial ovarian cancer associated with antihistamine use (≥2 prescriptions). The association was evaluated according to patterns of antihistamine use, menopausal status, and histological subtype of ovarian cancer. Results: Ever use of antihistamines was not associated with ovarian cancer overall (OR = 0.97, 95% CI = 0.90–1.05). The lack of association remained in subanalyses for patterns of antihistamine use. We observed an inverse association between antihistamine use and ovarian cancer among pre-menopausal women (

Background:\ud \ud Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.\ud Methods:\ud \ud We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.\ud Results:\ud \ud Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01–1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01–1.11) and borderline (pOR = 1.15; 95% CI: 1.02–1.29) tumours.\ud Conclusions:\ud \ud Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

Background: The safety of laparoscopic appendectomy for the management of incidentally discovered appendiceal tumors has not yet been established. Methods: Appendiceal tumor cases managed by laparoscopy or laparotomy over a 10-year period were reviewed. Results: The pathological diagnoses were 23 carcinoid and 20 cancerous lesions. The median patient ages were 36 and 69years, respectively, for carcinoid and other tumors (p < 0.05). Acute appendicitis was present in 70% of carcinoid cases and 35% of other tumors (p < 0.05). Eight patients with carcinoid tumors were operated on by laparoscopy, whereas 15 underwent laparotomy. Laparoscopic and open procedures were performed in three and 17 patients with cancerous lesions, respectively. Invaded surgical margins were seen after laparoscopy in 20% of patients and open surgery in 6%. Synchronous colon carcinoma was detected in 14% of the patients with an appendix neoplasm. The 5-year survival rates were similar after both laparoscopic and open appendectomy for either carcinoid or other tumors. Conclusion: Laparoscopic appendectomy for appendiceal tumors seems to have a slightly higher rate of inadequate resection. However, it is not associated with a significantly worse patient prognosis than open appendectomy

Background Endometriosis is known to harbor characteristics substantiating its possible role as a precursor of ovarian cancer. Objective To assess the quality of the literature regarding the association between endometriosis and ovarian cancer and to estimate the extent of this relation. Methods An electronic literature search was conducted in PubMed and 1112 articles dealing with the relation between endometriosis and ovarian cancer were identified. Original articles based on case-control studies, cohort studies and cross-sectional studies were included. Studies consisting of populations with self-reported endometriosis were excluded, as were articles with fewer than 20 cases of ovarian cancer. Twenty-eight studies underwent detailed quality assessments based on the checklists developed by the Scottish Intercollegiate Guidelines Network (SIGN). Meta-analyses were conducted on selected subgroups of ovarian cancer with coexisting endometriosis. Results None of the 28 studies was given the highest possible rating using the SIGN checklists. The risk of ovarian cancer in women with endometriosis was reported to be a standardized incidence ratio of 1.43–8.95, a rate ratio of 1.6–2.88, an odds ratio of 1.34, with a prevalence of ovarian cancer in 2.0–17.0% of women with endometriosis. Conversely, the prevalence of endometriosis in women with ovarian cancer ranged from 3.4 to 52.6%. Meta-analysis results were weakened by heterogeneity. Conclusion There is sufficient evidence to conclude that there is an increased risk of developing clear-cell and endometrioid epithelial ovarian cancer for women with histologically verified endometriosis. Nonetheless, prospective cohort studies assessing the relation between endometriosis and ovarian cancer will increase knowledge in this field.

We evaluated the impact of a family history of breast/ovarian cancer on the risk of secondary leukemia following breast cancer. At the Geneva cancer registry, we identified 4,397 patients diagnosed with invasive breast cancer between 1990 and 2004. Patients were followed up for leukemia until the end of 2005. Family history was categorized as positive in patients with >or=1 first- or second-degree relative with breast/ovarian cancer. We compared leukemia rates in patients with positive and negative family histories with those expected in the general population, generating standardized incidence ratios (SIRs). With Cox regression analysis, we calculated adjusted risks of secondary leukemia in patients with familial risks compared to those without it. Breast cancer patients had a significantly increased risk of secondary acute leukemia (SIR 3.2, 95% CI: 1.2-6.9) but not of chronic leukemia (SIR 1.6, 95% CI: 0.6-3.5). Among patients with a positive family history (n = 1.125, 25.6%), the SIRs were 5.7 (95% CI: 1.2-16.6) for acute and 5.2 (95% CI: 1.4-13.3) for chronic leukemia. Among breast cancer patients, family history was independently associated with leukemia [adjusted hazard ratio (HR(adj)) of 3.2, 95% CI: 1.1-9.2, among patient with vs. without family history]. The effect of family history was stronger for chronic leukemia (HR(adj): 11.6, 95% CI 1.3-104.7) than for acute leukemia (HR(adj) 1.6, 95% CI: 0.4-6.6). Breast cancer patients with a family history of breast/ovarian have an increased risk of secondary leukemia, both compared to the general population as well as to breast cancer patients without family histories. This excess risk is largely due to the increased risk of secondary chronic leukemia.

Between 1976 and 1996, 176 borderline ovarian tumours were registered in the Cancer Registry of the Swiss canton of Vaud, corresponding to an age-adjusted incidence (world standard) of 2.7 in 100 000. Incidence rose from 1.7 per 100 000 during 1976–81 to 2.7 per 100 000 during 1987–91, and then levelled off; 58% of cases were serous and 41% mucinous. Relative survival was 94% at 10 years; 18 second neoplasms were observed, compared with 10.3 expected, and there was a significant excess of invasive ovarian cancers (four observed, including three synchronous, compared with 0.4 expected). © 1999 Cancer Research Campaign