Prophylactic Salpingo-Opphorectomy in Patients With Hereditary Predisposition Genes for Ovarian Cancer.
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ABSTRACT:
SUBMITTER: Garrett AA
PROVIDER: S-EPMC9191378 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
Publications
Prophylactic Salpingo-Opphorectomy in Patients With Hereditary Predisposition Genes for Ovarian Cancer.
Garrett Alison A AA Mahdi Haider H
JCO oncology practice 20220308 6
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Project description:Pathogenic germline variants underlie up to 20% of ovarian cancer (OC) and are associated with varying degrees of risk for OC. For mutations in high-penetrance genes such as BRCA1/2, the role of risk-reducing bilateral salpingo-oophorectomy (RRSO) in cancer prevention is well-established and improves mortality. However, in moderate-penetrance genes where the degree of risk for OC is less precisely defined, the role of RRSO is more controversial. Although national guidelines have evolved to incorporate gene-specific recommendations, studies demonstrate significant variations in practice. Given this, our multidisciplinary group has reviewed the available literature on risk estimates for genes associated with OC, incorporated levels of evidence, and set thresholds for consideration of RRSO. We found that the benefit of RRSO is well-established for pathogenic variants in BRCA1/2 as well as BRIP1 and RAD51C/D where the risk of OC is elevated beyond our threshold for RRSO. In PALB2, RRSO is particularly controversial as newer studies consistently demonstrate an increased risk of OC that is dependent on family history, making uniform recommendations challenging. Additionally, new guidelines for Lynch syndrome provide gene-specific risks, questioning the role of RRSO, and even hysterectomy, for MSH6 and PMS2 mutation carriers. Given these uncertainties, shared decision making should be used around RRSO with discussion of individual risk factors, family history, and adverse effects of surgery and premature menopause. Herein, we provide a clinical guide and counseling points.
| S-EPMC8932494 | biostudies-literature
Project description:PurposeMany women with an elevated risk of hereditary breast and ovarian cancer have previously tested negative for pathogenic mutations in BRCA1 and BRCA2. Among them, a subset has hereditary susceptibility to cancer and requires further testing. We sought to identify specific groups who remain at high risk and evaluate whether they should be offered multi-gene panel testing.MethodsWe tested 300 women on a multi-gene panel who were previously enrolled in a long-term study at UCSF. As part of their long-term care, all previously tested negative for mutations in BRCA1 and BRCA2 either by limited or comprehensive sequencing. Additionally, they met one of the following criteria: (i) personal history of bilateral breast cancer, (ii) personal history of breast cancer and a first or second degree relative with ovarian cancer, and (iii) personal history of ovarian, fallopian tube, or peritoneal carcinoma.ResultsAcross the three groups, 26 women (9%) had a total of 28 pathogenic mutations associated with hereditary cancer susceptibility, and 23 women (8%) had mutations in genes other than BRCA1 and BRCA2. Ashkenazi Jewish and Hispanic women had elevated pathogenic mutation rates. In addition, two women harbored pathogenic mutations in more than one hereditary predisposition gene.ConclusionsAmong women at high risk of breast and ovarian cancer who have previously tested negative for pathogenic BRCA1 and BRCA2 mutations, we identified three groups of women who should be considered for subsequent multi-gene panel testing. The identification of women with multiple pathogenic mutations has important implications for family testing.
| S-EPMC5410210 | biostudies-literature
Project description:Hereditary predisposition to cancer concerns between 5% and 10% of cancers. The main genes involved in the most frequent syndromes (hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome) were identified in the 1990s. Exploration of their functional pathways then identified novel genes for hereditary predisposition to cancer, and candidate genes whose involvement remains unclear. To determine the contribution of truncating variants in 11 candidate genes (BARD1, FAM175A, FANCM, MLH3, MRE11A, PMS1, RAD50, RAD51, RAD51B, RINT1, and XRCC2) to cancer predisposition in a population of interest, panel sequencing was performed in 849 patients with a suspected hereditary predisposition to cancer for whom a diagnostic panel of 38 genes identified no causal mutation. Sixteen truncating variants were found in FANCM (n = 7), RINT1 (n = 4), RAD50 (n = 2), BARD1, PMS1, and RAD51B. FANCM (adjusted P-value: .03) and RINT1 (adjusted P-value: .04) were significantly associated with hereditary breast and ovarian cancer. However, further studies are required to determinate the risk of cancer, including the segregation of the variants in the families of our cases. No mutation was identified in RAD51, MRE11A, FAM175A, XRCC2, or MLH3. The involvement of these genes in the hereditary predisposition to cancer cannot be ruled out, although if it exists it is rare or does not seem to involve truncating variants.
| S-EPMC7756731 | biostudies-literature
Project description:ObjectivesThe causes of ovarian cancer (OC) have been confirmed to be closely related to genetic factors. Identifying sequence variants of hereditary ovarian cancer (HOC) susceptibility genes can increase clinical surveillance, facilitate early detection, and provide personalized treatment for patients. This study is aimed at investigating the variation frequency of HOC susceptibility genes in the Chinese population and providing information for the etiology and genetics of OC.Methods118 epithelial OC patients were recruited in this clinical study. Variants of 18-gene panel were detected in blood samples by next-generation sequencing (NGS) technology.ResultsOverall, 36.44% (43/118) of patients carried at least one pathogenic variant. Among these, BRCA1 pathogenic variants were detected in 31 (26.27%) patients, and 5 (4.24%) patients carried pathogenic variants of BRCA2. Moreover, 27.12% (32/118) of patients carried variants of unknown significance (VUSs). Importantly, we detected eight variants that were not reported previously.ConclusionsOur study enlarged the spectrum of HOC-associated gene sequence variants in the Chinese population and also proved the necessity of multigene testing in epithelial OC patients. The identification of patients with HOC will allow family members to undergo cascade testing where identification of unaffected carriers can facilitate early detection, risk reduction, or prevention of OC and ultimately improve long-term outcomes.
| S-EPMC8328723 | biostudies-literature
Project description:ImportanceFew studies have investigated whether prophylactic salpingo-oophorectomy (PSO) for patients with previously resected breast cancer who carry pathogenic germline BRCA1 or BRCA2 variants is associated with a reduced risk of cancer-specific death.ObjectiveTo assess the association of PSO and prophylactic mastectomy (PM) with prognosis after quadrantectomy or mastectomy as primary treatment for patients with BRCA1 or BRCA2 breast cancer.Design, setting, and participantsThis retrospective cohort study was performed in a single-institution, tertiary referral center. Consecutive patients with invasive breast cancer treated surgically between 1972 and 2019 were recruited and followed up prospectively after they were found to carry the BRCA1 or BRCA2 gene variant. The data analysis was performed between April 2022 and July 2023.ExposureFollowing breast surgery, some patients underwent PSO, PM, or both, whereas others did not.Main outcomes and measuresThe primary study end point was overall survival as measured by the Kaplan-Meier method. Secondary end points were crude cumulative incidence of breast cancer-specific mortality, ipsilateral breast tumor recurrence (IBTR), contralateral breast cancer, ovarian cancer, and ovarian cancer-specific mortality.ResultsOf 480 patients included in the cohort (median age at initial surgery, 40.0 years; IQR, 34.0-46.0 years), PSO was associated with a significantly reduced risk of death (hazard ratio [HR], 0.40; 95% CI, 0.25-0.64; P < .001). This reduction was most evident for patients carrying the BRCA1 variant (HR, 0.35; 95% CI, 0.20-0.63; P = .001), those with triple-negative disease (HR, 0.21; 95% CI, 0.09-0.46; P = .002), and those with invasive ductal carcinoma (HR, 0.51; 95% CI, 0.31-0.84; P = .008). Prophylactic salpingo-oophorectomy was not associated with risk of contralateral breast cancer or IBTR. Initial or delayed PM was associated with a reduced risk of IBTR but not with overall survival or breast cancer-specific mortality.ConclusionsThe study findings suggest that PSO should be offered to all patients with BRCA1/2 breast cancer who undergo surgery with curative intent to reduce risk of death. In particular, PSO should be offered to patients with the BRCA1 variant at the time of breast surgery.
| S-EPMC10551816 | biostudies-literature
Project description:BackgroundBreast, colorectal, ovarian, and endometrial cancers constitute approximately 30% of newly diagnosed cancer cases in Switzerland, affecting more than 12,000 individuals annually. Hundreds of these patients are likely to carry germline pathogenic variants associated with hereditary breast ovarian cancer (HBOC) or Lynch syndrome (LS). Genetic services (counseling and testing) for hereditary susceptibility to cancer can prevent many cancer diagnoses and deaths through early identification and risk management.ObjectiveCascade screening is the systematic identification and testing of relatives of a known mutation carrier. It determines whether asymptomatic relatives also carry the known variant, needing management options to reduce future harmful outcomes. Specific aims of the CASCADE study are to (1) survey index cases with HBOC or LS from clinic-based genetic testing records and determine their current cancer status and surveillance practices, needs for coordination of medical care, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to serve as advocates for cancer genetic services to blood relatives, (2) survey first- and second-degree relatives and first-cousins identified from pedigrees or family history records of HBOC and LS index cases and determine their current cancer and mutation status, cancer surveillance practices, needs for coordination of medical care, barriers and facilitators to using cancer genetic services, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to participate in a study designed to increase use of cancer genetic services, and (3) explore the influence of patient-provider communication about genetic cancer risk on patient-family communication and the acceptability of a family-based communication, coping, and decision support intervention with focus group(s) of mutation carriers and relatives.MethodsCASCADE is a longitudinal study using surveys (online or paper/pencil) and focus groups, designed to elicit factors that enhance cascade genetic testing for HBOC and LS in Switzerland. Repeated observations are the optimal way for assessing these outcomes. Focus groups will examine barriers in patient-provider and patient-family communication, and the acceptability of a family-based communication, coping, and decision-support intervention. The survey will be developed in English, translated into three languages (German, French, and Italian), and back-translated into English, except for scales with validated versions in these languages.ResultsDescriptive analyses will include calculating means, standard deviations, frequencies, and percentages of variables and participant descriptors. Bivariate analyses (Pearson correlations, chi-square test for differences in proportions, and t test for differences in means) will assess associations between demographics and clinical characteristics. Regression analyses will incorporate generalized estimating equations for pairing index cases with their relatives and explore whether predictors are in direct, mediating, or moderating relationship to an outcome. Focus group data will be transcribed verbatim and analyzed for common themes.ConclusionsRobust evidence from basic science and descriptive population-based studies in Switzerland support the necessity of cascade screening for genetic predisposition to HBOC and LS. CASCADE is designed to address translation of this knowledge into public health interventions.Trial registrationClinicalTrials.gov NCT03124212; https://clinicaltrials.gov/ct2/show/NCT03124212 (Archived by WebCite at http://www.webcitation.org/6tKZnNDBt).
| S-EPMC5628286 | biostudies-literature
Project description:Male breast cancer (mBC) is associated with a high prevalence of pathogenic variants (PVs) in the BRCA2 gene; however, data regarding other BC predisposition genes are limited. In this retrospective multicenter study, we investigated the prevalence of PVs in BRCA1/2 and 23 non-BRCA1/2 genes using a sample of 614 patients with mBC, recruited through the centers of the German Consortium for Hereditary Breast and Ovarian Cancer. A high proportion of patients with mBC carried PVs in BRCA2 (23.0%, 142/614) and BRCA1 (4.6%, 28/614). The prevalence of BRCA1/2 PVs was 11.0% in patients with mBC without a family history of breast and/or ovarian cancer. Patients with BRCA1/2 PVs did not show an earlier disease onset than those without. The predominant clinical presentation of tumor phenotypes was estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, and HER2-negative (77.7%); further, 10.2% of the tumors were triple-positive, and 1.2% were triple-negative. No association was found between ER/PR/HER2 status and BRCA1/2 PV occurrence. Comparing the prevalence of protein-truncating variants (PTVs) between patients with mBC and control data (ExAC, n = 27,173) revealed significant associations of PTVs in both BRCA1 and BRCA2 with mBC (BRCA1: OR = 17.04, 95% CI = 10.54-26.82, p < 10-5; BRCA2: OR = 77.71, 95% CI = 58.71-102.33, p < 10-5). A case-control investigation of 23 non-BRCA1/2 genes in 340 BRCA1/2-negative patients and ExAC controls revealed significant associations of PTVs in CHEK2, PALB2, and ATM with mBC (CHEK2: OR = 3.78, 95% CI = 1.59-7.71, p = 0.002; PALB2: OR = 14.77, 95% CI = 5.02-36.02, p < 10-5; ATM: OR = 3.36, 95% CI = 0.89-8.96, p = 0.04). Overall, our findings support the benefit of multi-gene panel testing in patients with mBC irrespective of their family history, age at disease onset, and tumor phenotype.
| S-EPMC9265404 | biostudies-literature
Project description:BackgroundHereditary breast and ovarian cancers (HBOCs) pose significant health risks worldwide and are mitigated by prophylactic interventions. However, a meta-analysis of their efficacy and the impact of different genetic variants on their effectiveness is lacking.MethodsA systematic review and meta-analysis were conducted, adhering to Cochrane guidelines. The review encompassed studies that involved prophylactic interventions for healthy women with BRCA variants, focusing on cancer incidence and mortality outcomes. The Newcastle-Ottawa Scale was used for risk of bias assessment. We pooled the extracted outcomes using random effects models and conducted subgroup analyses stratified by intervention, variant, and cancer types.ResultsA total of 21 studies met the inclusion criteria. The meta-analysis revealed that prophylactic interventions significantly reduced cancer risk and mortality. The subgroup analysis showed a greater protective effect for BRCA2 than BRCA1 variant carriers. Risk-reducing surgeries (RRS) were more effective than chemoprevention, with RRS notably reducing cancer risk by 56% compared to 39% for chemoprevention. Prophylactic oophorectomy significantly reduced HBOC risks, while the effect of prophylactic mastectomy and chemoprevention on mortality was less conclusive.ConclusionsProphylactic interventions significantly reduce the risk of HBOC and associated mortality. This comprehensive analysis provides insights for future economic evaluations and clinical decision-making in HBOC interventions.
| S-EPMC10778044 | biostudies-literature
Project description:ObjectiveApproximately 5%-10% of breast cancer (BC) patients display familial traits that are genetically inherited among the members of a family. The purpose of this study was to profile the germline mutations in 43 genes with different penetration rates and their correlations with phenotypic traits in Chinese familial BC families.MethodsIon Torrent S5™-based next generation sequencing was conducted on 116 subjects from 27 Chinese familial BC families.ResultsEighty-one germline mutations in 27 BC predisposition genes were identified in 82.8% (96/116) of the cases. Among these, 80.8% of the mutated genes were related to DNA damage repair. Fourteen possible disease-causing variants were identified in 13 of 27 BC families. Only 25.9% (7/27) of the BC families exhibited hereditary deficiency in BRCA1/2 genes, while 22.2% of the BC families exhibited defects in non-BRCA genes. In all, 41.7% (40/96) of the mutation carriers had BRCA mutations, 88.5% (85/96) had non-BRCA mutations, and 30.2% (29/96) had both BRCA and non-BRCA mutations. The BC patients with BRCA mutations had a higher risk of axillary lymph node metastases than those without mutations (P < 0.05). However, the BC patients with non-BRCA mutations frequently had a higher occurrence of benign breast diseases than those without mutations (P < 0.05).ConclusionsIn addition to BRCA1/2, genetic variants in non-BRCA DNA repair genes might play significant roles in the development of familial/hereditary BC. Therefore, profiling of multiple BC predisposition genes should be more valuable for screening potential pathogenic germline mutations in Chinese familial/hereditary BC.
| S-EPMC9257317 | biostudies-literature
Project description:Despite the identification of several ovarian cancer (OC) predisposition genes, a large proportion of familial OC risk remains unexplained. We adopted a two-stage design to identify new OC predisposition genes. We first carried out a large germline whole-exome sequencing study on 158 patients from 140 families with significant OC history, but without evidence of genetic predisposition due to BRCA1/2. We then evaluated the potential candidate genes in a large case-control association study involving 381 OC cases in the Cancer Genome Atlas project and 27,173 population controls from the Exome Aggregation Consortium. Two new putative OC risk genes were identified, namely, ANKRD11, a putative tumor suppressor, and POLE, an enzyme involved in DNA repair and replication. These two genes likely confer moderate OC risk. We performed in vitro experiments and showed an ANKRD11 mutation identified in our patients markedly lowered the protein expression by compromising protein stability. Upon future validation and functional characterization, these genes may shed light on cancer etiology along with improving ascertainment power and preventive care of individuals at high risk of OC.
| S-EPMC7065147 | biostudies-literature