scholarly journals Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3468
Author(s):  
Gulisa Turashvili ◽  
Conxi Lazaro ◽  
Shengjie Ying ◽  
George Charames ◽  
Andrew Wong ◽  
...  
Keyword(s):  
Success Rate ◽  
Limit Of Detection ◽  
Brca Mutation ◽  
Mutation Rates ◽  
Serous Carcinoma ◽  
Sample Type ◽  
High Grade ◽  
Brca Testing ◽  
Cancer Syndrome ◽  
Tissue Samples

Background: Approximately 25% of women diagnosed with tubo-ovarian high-grade serous carcinoma have germline deleterious mutations in BRCA1 or BRCA2, characteristic of hereditary breast and ovarian cancer syndrome, while somatic mutations have been detected in 3–7%. We set out to determine the BRCA mutation rates and optimal tissue requirements for tumor BRCA testing in patients diagnosed with tubo-ovarian high-grade serous carcinoma. Methods: Sequencing was performed using a multiplexed polymerase chain reaction-based approach on 291 tissue samples, with a minimum sequencing depth of 500X and an allele frequency of >5%. Results: There were 253 surgical samples (87%), 35 biopsies (12%) and 3 cytology cell blocks (1%). The initial failure rate was 9% (25/291), including 9 cases (3%) with insufficient tumor, and 16 (6%) with non-amplifiable DNA. Sequencing was successful in 78% (228/291) and deemed indeterminate due to failed exons or variants below the limit of detection in 13% (38/291). Repeat testing was successful in 67% (28/42) of retested samples, with an overall success rate of 86% (251/291). Clinically significant (pathogenic, likely pathogenic) variants were identified in 17% (48/276) of complete and indeterminate cases. Successful sequencing was dependent on sample type, tumor cellularity and size (p ≤ 0.001) but not on neoadjuvant chemotherapy or age of blocks (p > 0.05). Conclusions: Our study shows a 17% tumor BRCA mutation rate, with an overall success rate of 86%. Biopsy and cytology samples and post-chemotherapy specimens can be used for tumor BRCA testing, and optimal tumors measure ≥5 mm in size with at least 20% cellularity.

scholarly journals 4D Doppler Ultrasound in High Grade Serous Ovarian Cancer Vascularity Evaluation—Preliminary Study

Diagnostics ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 582
Author(s):  
Marek Jerzy Kudla ◽  
Michal Zikan ◽  
Daniela Fischerova ◽  
Mateusz Stolecki ◽  
Juan Luis Alcazar
Keyword(s):  
Ovarian Cancer ◽  
Malignant Tumors ◽  
Menopausal Status ◽  
Power Doppler ◽  
Serous Carcinoma ◽  
Benign Tumors ◽  
Control Group ◽  
High Grade ◽  
Tissue Samples ◽  
4D Ultrasound

The aim of the study was to evaluate the usefulness of 4D Power Doppler tissue evaluation to discriminate between normal ovaries and ovarian cancer tumors. This was a prospective observational study. Twenty-three cases of surgically confirmed ovarian High Grade Serous Carcinoma (HGSC) were analyzed. The control group consisted of 23 healthy patients, each matching their study-group counterpart age wise (±3 years) and according to their menopausal status. Transvaginal Doppler 4D ultrasound scans were done on every patient and analyzed with 3D/4D software. Two 4D indices—volumetric Systolic/Diastolic Index (vS/D) and volumetric Pulsatility Index (vPI)—were calculated. To keep results standardized and due to technical limitations, virtual 1cc spherical tissue samples taken from the part with highest vascularization as detected by bi-directional Power Doppler were analyzed for both groups of ovaries. Values of volumetric S/D indices and volumetric PI indices were statistically lower in ovarian malignant tumors compared to normal ovaries: 1.096 vs. 1.794 and 0.092 vs. 0.558, respectively (p < 0.001). The 4D bi-directional Power Doppler vascular indices were statistically different between malignant tumors and normal ovaries. These findings could support the rationale for future studies for assessing this technology to discriminate between malignant and benign tumors.

Validation of BRCA testing on cytologic samples of high‐grade serous carcinoma

2021 ◽  
Author(s):  
Si Kei Lou ◽  
Sylvie Grenier ◽  
Melanie Care ◽  
Jeanna McCuaig ◽  
Tracy L. Stockley ◽  
...  
Keyword(s):  
Serous Carcinoma ◽  
High Grade ◽  
Brca Testing

scholarly journals Preneoplastic Lesions Fimbria Early Diagnosis Markers Underlying Timeline Mechanisms at The Origin of Ovarian Cancer in BRAC1/2 Patients: Case Reports Based on Proteogenomic Study

2021 ◽  
Author(s):  
Maxence Wisztorski ◽  
Philippe Saudemont ◽  
Soulaimane Aboulouard ◽  
Tristan Cardon ◽  
Fabrice Narducci ◽  
...  
Keyword(s):  
Case Reports ◽  
Brca Mutation ◽  
Hormone Replacement ◽  
Serous Carcinoma ◽  
Surgical Removal ◽  
High Grade ◽  
Fallopian Tubes ◽  
Preneoplastic Lesions ◽  
Ovarian Carcinomas ◽  
Cancer Pathogenesis

Abstract Background : BRCA 1 or 2 mutations have been known to be drivers of high-grade serous ovarian carcinomas (HGSC). As no efficient screening is currently available, a bilateral prophylactic salpingo-oophorectomy is the recommended procedure to avoid this often lethal carcinomas. However, a proportion of BRCA mutation carriers refuse to undergo this procedure due to significant impacts on quality and quantity of life, especially if a hormone replacement therapy is contra-indicated. Such decision expose them to developing a pelvic serous carcinoma. A better undersanding of high-grade serous cancer pathogenesis, rather stemming from fallopian tubes than from ovary itself, makes interesting a two-step prophylactic strategy in which tubes are removed as soon as possible, followed by oophorectomies at the time of menopause. Thus women are protected against HGSC with no immediate need of an HRT. Following this idea and considering the concept of junctional “hot spots “ (called mesothelo-müllerian junctions) for the development of HGSC, we suggested as first step to perform a bilateral prophylactic radical fimbriectomy rather than salpingectomy with a delayed oophorectomy (RF/DO). This operation was tested in a national phase 2 trial from 2011-2014 (NCT01608074). Radical Fimbriectomy (RF) consists of the surgical removal of both fallopian tubes along with a tiny part of the adherent ovary to suppress the tubal source of possible dysplastic cells from which can stem a high-grade invasive tumor, through stepwise cellular and genomic altereations ranging from p53 signatures to serous tubal intraepithelial carcoinoma (STIC), just before genuine invasive HGSC, through intermediate aspects (STIL) and (TILT). Methods : In this context, we carried out an in-depth proteomics analysis of these “pre-invasive ” epithelial lesions based on spatially resolved proteomic/ and bioinformatics systems biology platforms platform guided by immunohistochemistry (IHC) technique. Results : Specific markers related to each preneoplastic lesions and in particular from normal to p53 signatures were evaluated. We identified EIF3B, MOB1B and Emilin2, CAVIN1 as bad prognosis markers of P53 signature whereas CAVIN2, SPTANi, FBLN5 as good prognosis markers. Among the novel markers identified, mutated proteins as well as hidden proteins translated from alternative ORF Proteome have been sequenced and characterized. Conlusion : In summary, our results represent a novel pioneer approach to identify the unique under investigated markers that can characterize the molecular mechanism occurring in the preneoplastic lesion in fimbria at the origin of the HGSC.

scholarly journals Somatic BRCA Mutation in High Grade Epithelial Ovarian Cancer Patients

2019 ◽  
Vol 3 (4) ◽  
pp. 99-103
Author(s):  
Tarinee Manchana ◽  
Ruangsak Lertkhachonsuk ◽  
Chinachote Teerapakpinyo
Keyword(s):  
Peripheral Blood ◽  
Brca Mutation ◽  
Brca1 Mutation ◽  
Serous Carcinoma ◽  
High Grade ◽  
Fallopian Tube Cancer ◽  
Peritoneal Cancer ◽  
Tumor Tissues ◽  
Germline Brca Mutation ◽  
Poorly Differentiated

Aim: To identify the frequency of somatic BRCA mutation in epithelial ovarian cancer (EOC), particularly those with high grade subtypes. Methods: Patients diagnosed with EOC included fallopian tube cancer or peritoneal cancer who had surgery during January 2015 to December 2016 were included. High grade subtypes included high grade serous carcinoma, poorly differentiated endometrioid carcinoma, and clear cell carcinoma. BRCA1 and BRCA2 mutations were tested using DNA extracted from formalin-fixed paraffin embedded block or a fresh tumor specimen then analyzed by next generation sequencing system. Patients who had no germline BRCA mutation in their peripheral blood DNA investigated by bi-directional Sanger sequencing were diagnosed as having somatic BRCA mutation.Results: 36 patients were enrolled; majority of the patients (33patients; 97.2%) had EOC, 1 patient (2.8%) had fallopian tube cancer and 2 patients (5.6%) had peritoneal cancer. 28 patients (77.8%) had high grade serous carcinoma, 6 (16.7%) had poorly differentiated endometrioid carcinoma, and 2 (5.6%) had clear cell carcinoma. BRCA1 mutation was detected in tumor tissues of 2 patients (5.6%). These two patients had high grade serous carcinoma and significant family history of breast and/or ovarian cancers. However, BRCA1 mutations were detected in the peripheral blood in both of them.Conclusion: Only 5.6% of BRCA1 mutation was detected in ovarian tumor tissues, all mutations were found in high grade serous subtype. However, BRCA mutations were detected in the peripheral blood in both of them. Germline BRCA mutation was diagnosed, thus there were no somatic mutations in this study.

Testing of BRCA 1/2 gene mutations in FFPE samples of patients with high-grade serous ovarian cancer and limits of its bioinformatic interpretation.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17060-e17060
Author(s):  
Katarina Janikova ◽  
Zora Lasabova ◽  
Marian Grendar ◽  
Anna Farkasova ◽  
Karla Scheerova ◽  
...  
Keyword(s):  
Brca Mutation ◽  
Gene Mutations ◽  
Serous Carcinoma ◽  
High Grade ◽  
Sequencing Data ◽  
Bioinformatic Tools ◽  
Ffpe Samples ◽  
Low Coverage ◽  
Simultaneous Identification

e17060 Background: BRCA1/2 mutations represent first genetically defined predictive markers for targeted therapy of patients with recurrent high-grade serous carcinoma (HGSC), therefore patients with HGSC should be tested for a germline and somatic BRCA mutation (g BRCAm and s BRCAm, resp.). In our study we analyzed possibilities and limits for determination of both origin and pathogenicity of mutations detected by HGSC biopsies analyses. Methods: We present data obtained by massive parallel sequencing on Miseq (Illumina). Library for sequencing was prepared by Somatic BRCA Tumor MASTR Plus kit (Multiplicom) from DNA isolated from HGSC FFPE tissue of 42 patients allowing simultaneous identification of g BRCAm and s BRCAm. For the pathogenicity evaluations we followed American College of Medical Genetics and Genomics (ACMG) criteria and used various bioinformatic tools. Results: All sequencing data were interpreted by SOPHIA DDM (Sophia Genetics) commercial tool. BRCA1/2 mutation was absent in 43% and present in 50% of patients, while 7% of cases had to be retested due to low coverage. Data of 28/42 patients were analyzed also by Ingenuity (Qiagen), the comparison of both the tools identified discrepant pathogenic determinationin 29% of them. The discrepancies in origin and pathogenicity of already detected mutations were found also by analyzing the data in other non-commercial databases (dbSNP, COSMIC, ClinVar, BIC, etc.). Conclusions: At least in a certain proportion of the cases, the data obtained by HGSC biopsy specimen mutational analyses and interpreted by accessible bioinformatic tools may lead to an equivocal assessment of both origin and pathogenicity of detected BRCA1/2 mutations. Other studies are necessary to eliminate the observed discrepancies.

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