Abstract POSTER-CTRL-1208: A dualistic model for the origin of high-grade serous carcinoma: BRCA mutation status, histology and tubal intraepithelial carcinoma

2015 ◽  
Author(s):  
Brooke E Howitt ◽  
Suchanan Hanamornroongruang ◽  
Douglas Lin ◽  
James E Conner ◽  
Stephanie Schulte ◽  
...  
Keyword(s):  
Brca Mutation ◽  
Serous Carcinoma ◽  
High Grade ◽  
Mutation Status ◽  
Intraepithelial Carcinoma

scholarly journals High-Grade Serous Ovarian Cancer: Associations between BRCA Mutation Status, CT Imaging Phenotypes, and Clinical Outcomes

Radiology ◽  
2017 ◽  
Vol 285 (2) ◽  
pp. 472-481 ◽  
Author(s):  
Stephanie Nougaret ◽  
Yulia Lakhman ◽  
Mithat Gönen ◽  
Debra A. Goldman ◽  
Maura Miccò ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Outcomes ◽  
Brca Mutation ◽  
Ct Imaging ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Mutation Status

Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance

2008 ◽  
Vol 18 (3) ◽  
pp. 487-491 ◽  
Author(s):  
R. SALANI ◽  
R. J. KURMAN ◽  
R. GIUNTOLI ◽  
G. GARDNER ◽  
R. BRISTOW ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mutation Frequency ◽  
Clinical Stage ◽  
Serous Carcinoma ◽  
Low Grade ◽  
High Grade ◽  
Mutation Status ◽  
Tumor Dna ◽  
Serous Tumors

The TP53 mutation frequency in ovarian serous carcinomas has been reported to range between 50% and 80%, but a stringent analysis of TP53 using purified epithelial samples has not yet been performed to accurately assess the mutation frequency and to correlate it with the histologic grade. The purpose of this study was to assess the TP53 mutational profile in a relatively large series of high-grade (53 primary and 18 recurrent) and 13 low-grade ovarian serous tumors using DNA isolated from affinity-purified tumor cells and to correlate it with in vitro drug resistance. All samples were affinity purified, and the tumor DNA was analyzed for TP53 mutations in exons 4–9. In vitro drug resistance assays to carboplatin, cisplatin, paclitaxel, and taxotere were performed on the same tumor samples and correlated with the TP53 mutation status. TP53 mutations were detected in 57 (80.3%) of 71 high-grade carcinomas and in one (7.8%) of 13 low-grade serous tumors (an invasive low-grade serous carcinoma). The mutations were predominantly missense mutations (59.6%). TP53 mutations were associated with high-grade serous carcinomas and recurrent disease (P < 0.0001). There was no statistically significant correlation between TP53 mutation status and drug resistance assays or clinical stage (P > 0.25). The frequency of TP53 mutations using purified tumor DNA from ovarian serous carcinomas was 80.3%, which is much higher than previously reported. Furthermore, we found that TP53 is not directly involved in the development of drug resistance in high-grade ovarian serous carcinomas.

Changes in the Extracellular Matrix Are Associated With the Development of Serous Tubal Intraepithelial Carcinoma Into High-Grade Serous Carcinoma

2017 ◽  
Vol 27 (6) ◽  
pp. 1072-1081 ◽  
Author(s):  
Sophieke C.H.A. van der Steen ◽  
Johan Bulten ◽  
Koen K. Van de Vijver ◽  
Toin H. van Kuppevelt ◽  
Leon F.A.G. Massuger
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Serous Carcinoma ◽  
High Grade ◽  
Full Spectrum ◽  
Preinvasive Lesions ◽  
Intraepithelial Carcinoma ◽  
Screening And Prevention ◽  
Step Transition ◽  
Intraepithelial Lesions

ObjectiveThe identification of a marker for early progression of preinvasive lesions into invasive pelvic high-grade serous carcinoma (HGSC) may provide novel handles for innovative screening and prevention strategies. The interplay between cancer cells and the extracellular matrix (ECM) is one of the main principles in cancer development and growth, but has been largely neglected in preinvasive lesions. This is the first study addressing the involvement of the ECM in the “step-by-step” transition of normal fallopian tube epithelium into preinvasive lesions, and eventually the progression of preinvasive lesions into invasive HGSC.MethodsThe expression of highly sulfated chondroitin sulfate (CS-E), a characteristic glycosaminoglycan of the cancer-associated ECM, was assessed by immunohistochemistry in a large cohort of precursor lesions of the full spectrum of HGSC development, including 97 serous tubal intraepithelial carcinomas (STICs), 27 serous tubal intraepithelial lesions, and 24 p53 signatures. In addition, the immunological reactivity in the microenvironment was evaluated.ResultsIncreased stromal expression of highly sulfated CS-E was observed in 3.7%, 57.7%, and 90.6% of serous tubal intraepithelial lesions, STICs, and invasive HGSCs, respectively (P < 0.001). No or limited expression was found in p53 signatures and normal tubal epithelium (compared with STIC, P < 0.001). A gradual increase in the amount of CS-E expression between STIC and paired HGSC was demonstrated. Intense stromal CS-E expression in STIC was significantly associated with an immune infiltrate (P < 0.001).ConclusionsOur study showed that increased stromal CS-E expression is related to the degree of the tubal epithelium abnormality. Specific alterations in the ECM (ie, CS-E expression) occur early in pelvic HGSC development and may represent a novel biomarker of early cancer progression, useful for the identification of novel clinical strategies.

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.

Glucocorticoid receptor expression is associated with inferior overall survival independent of BRCA mutation status in ovarian cancer

2019 ◽  
Vol 29 (2) ◽  
pp. 357-364 ◽  
Author(s):  
Jennifer Taylor Veneris ◽  
Lei Huang ◽  
Jane E Churpek ◽  
Suzanne D Conzen ◽  
Gini F Fleming
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Overall Survival ◽  
Glucocorticoid Receptor ◽  
Cancer Patients ◽  
Brca Mutation ◽  
Receptor Expression ◽  
High Grade ◽  
Mutation Status ◽  
Relationship Of

ObjectiveHigh glucocorticoid receptor (GR) protein expression is associated with decreased progression-free survival in ovarian cancer patients and decreased sensitivity to chemotherapy in preclinical models. Prior studies suggest wild type BRCA1 promotes GR activation. The objective of this study was to characterize the relationship of tumor GR gene expression to outcome in ovarian cancer, and to evaluate the relationship of GR expression with BRCA status.MethodsWhole exome and whole genome sequencing, gene expression, and clinical data were obtained for high-grade serous ovarian cancers in The Cancer Genome Atlas. Cases with pathogenic somatic or germline BRCA1 or BRCA2 mutations were identified and classified as BRCA mutated. High or low glucocorticoid receptor expression was defined as expression above or below median of the GR/nuclear receptor subfamily 3 C1 (NR3C1) gene level. Overall survival was estimated by the Kaplan-Meier method and compared by Cox regression analysis.ResultsCombined germline DNA sequencing and tumor microarray expression data were available for 222 high-grade serous ovarian cancer cases. Among these, 47 had a deleterious germline and/or somatic mutation in BRCA1 or BRCA2. In multivariate analysis, high glucocorticoid receptor gene expression was associated with decreased overall survival among ovarian cancer patients, independently of BRCA mutation status. No correlation of GR/NR3C1 gene expression with BRCA mutation status or BRCA1 or BRCA2 mRNA level was observed.ConclusionsIncreased GR gene expression is associated with decreased overall survival in ovarian cancer patients, independently of BRCA mutation status. High-grade serous ovarian cancers with high GR expression and wild type BRCA have a particularly poor outcome.

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