Comprehensive analysis of germline and somatic BRCA1/2 mutations in ovarian cancer population: Interim results of OVATAR prospective study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23109-e23109 ◽  
Author(s):  
Alexandra Tyulyandina ◽  
Tatiana Kekeeva ◽  
Vera Karaseva ◽  
Vera Gorbunova ◽  
Larisa Kolomiets ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
Tumor Tissue ◽  
Rare Event ◽  
Brca Mutations ◽  
Tissue Samples ◽  
Large Deletions ◽  
Important Approach ◽  
Somatic Alterations ◽  
Next Generation Sequencing Ngs

e23109 Background: The most promising method for the detection of BRCA 1/2 mutations is next-generation sequencing (NGS). There is no enough data about prevalence of large deletions of BRCA mutations and somatic alterations in ovarian cancer (OC). NGS technology is important approach for somatic mutations search in tissue samples. Methods: 498 pts with serous and endometrioid OC were enrolled in OVATAR study (NCT02122588). NGS testing of BRCA1/2 in blood and tumor tissue, multiplex ligation-dependent probe amplification (MLPA) for large deletions in blood were employed. Results: Interim analysis included pair tumor and blood samples from 336 pts (median age 54 (22 - 84) years; family history in 79 (23.5%). The total rate of BRCA1/2 mutations was 29.2% (98/336) pts including 80.6% (79/98) germline mutations and 19.4% (19/98) somatic mutations. Hotspot mutations were detected in 42/98 (42.8%) pts, among them 5382insC mutation was observed in 29.6% (29/98). Blood MLPA was performed in 142 (42.2%) pts; germline large deletions were found in 2 (1.4%) cases. Differences in NGS results for tumor and blood are listed in the table. Conclusions: Application of NGS revealed rare mutations in 57.2% among all detected mutations in OC pts; moreover, NGS in tumor tissue provided a significant increase in BRCA mutations of 19% due to somatic alterations. Large deletions in BRCA1/2 are rare event in OC in our study. [Table: see text]

Prognostic value of epithelial cell adhesion molecule (EpCAM) in patients with primary epithelial ovarian cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15531-e15531
Author(s):  
Hannah Woopen ◽  
Klaus Pietzner ◽  
Rolf Richter ◽  
Christina Fotopoulou ◽  
Thomas Joens ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Epithelial Ovarian Cancer ◽  
Prognostic Marker ◽  
Tumor Tissue ◽  
Cancer Tissue ◽  
Complex Method ◽  
Tissue Samples ◽  
Epcam Expression ◽  
Primary Epithelial Ovarian Cancer

e15531 Background: EpCAM, a well known cancer antigene is currently experiencing a renaissance in its use as a binding site for targeted oncologic therapy and prognostic marker in various epithelial carcinomas such as breast cancer or carcinomas of the oral cavity. Goal of this retrospective study was to identify EpCAM as a potential prognostic marker for patients with primary epithelial ovarian cancer (EOC). Methods: EpCAM expression was assessed in tumor tissue by immunohistochemistry using the Avidin-Biotin-Complex method on paraffin-embedded ovarian cancer tissue samples. EpCAM overexpression was defined as an expression of EpCAM as high as 76-100%. Clinical data as well as tumor tissue samples were collected within the validated “Tumor bank Ovarian Cancer Network (TOC)”. Results: Seventy-four patients with the primary diagnosis of EOC between 01/1994 and 12/2009 were included in this study. Median age at diagnosis was 56 years. The vast majority of the patients (75.4%) presented an advanced stage disease (FIGO III/IV). Forty-one (55.4%) patients were diagnosed with a serous, 19 (25.6%) a endometrioid and 14 (19%) a mucinous histology. EpCAM was overexpressed in 87.7% of the patients. Serous tumors expressed EpCAM in significantly higher rates than mucinous tumors ( p=0.045). EpCAM overexpression correlated in univariate analysis with a significantly better overall survival. Multivariate analysis including histological subtype identified EpCAM expression of 76-100% to be independently associated with a significantly better overall survival compared to a lower EpCAM expression of ≤50% (p=0.008). Conclusions: EpCAM overexpression in EOC appears to be associated with significantly higher overall survival rates. Larger, prospectively assessed multicenter studies are warranted to further evaluate and confirm these novel findings and possibly establish EpCAM as a potent therapeutic target in EOC.

Somatic versus germline BRCA mutations screening in ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13100-e13100
Author(s):  
Hugo SM Nunes ◽  
Patricia Machado ◽  
Sofia Fragoso ◽  
Sidonia Santos ◽  
Fernanda Silva ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
Brca Mutation ◽  
Point Mutations ◽  
Parp Inhibitors ◽  
Brca Mutations ◽  
Alu Element ◽  
Brca1 Carriers ◽  
Large Rearrangements ◽  
Clinic Medical

e13100 Background: ovarian cancer (OC) with germinal or somatic BRCA mutations responds better to platinum and to PARP-inhibitors. There is great enthusiasm about BRCA somatic screening. Our aim was to analyse the correlation between BRCA somatic and germline mutational profile. Methods: a cohort of 23 pts was obtained by cross-linking OC pts from the South Portuguese Cancer Registry, between 2009-2014 and BRCA mutation carriers identified in our Clinic. Medical records were reviewed: demographic and clinico-pathologic data obtained. Germinal screening: pts were pre-screened for the BRCA2 Portuguese founder mutation (PFM), analysed for BRCA point mutations (different screening methodologies were used in diagnostic timeline: initially CSGE, then CSCE and finally NGS) and for large rearrangements by MLPA. Somatic screening: DNA was extracted from 5 sections of 10µm of FFPE tissue and analysed for BRCA1/2 genes by NGS. Results: clinico-pathological features of the 23 pts revealed mainly high-grade serous histology (96%). Mean age at diagnosis was 54 years old (33-76); BRCA2 were older than BRCA1 carriers (62 vs 51). Most pts presented at advanced stage (70% stages III-IV; 30% stage I-II). Seventeen were BRCA1 carriers and 6 were BRCA2 (5 of those PFM, a large insertion of an Alu element). Somatic correlation: 8 pts (5 BRCA1, 3PFM) were already analysed and 100% correlation was observed for all point mutations. One additional BRCA2 somatic mutation was detected (with a variant allele frequency of 53% whereas 2 others were < 7%); interestingly exclusive somatic mutations were only observed in PFM carriers (known not to be NGS detectable). The remaining 15 pts are under analysis. Conclusions: it was expected that the PFM and other large rearrangements would not be detected with NGS. A specific somatic screening for the PFM may be possible but other rearrangements are found by MLPA in our population (10% of all BRCA mutations). Preliminary data adds to the evidence that NGS OC somatic screening will identify all germinal point mutations and an indeterminate number of additional pts with exclusive somatic mutations. An ideal correlation needs integration of differenttechniques that may increase complexity, time and cost.

scholarly journals UP-Regulation of Dicer and Drosha Expression in Ovarian Cancer Tissues

2021 ◽  
Author(s):  
sanaz razmkhah
Keyword(s):  
Ovarian Cancer ◽  
Tumor Tissue ◽  
Clinicopathological Characteristics ◽  
Rate Of Change ◽  
Tissue Samples ◽  
Surgical Department ◽  
Cellular Processes ◽  
Significant Difference ◽  
Cancer Tissues ◽  
The Impact

Abstract BACKGROUND: miRNAs show to play fundamental roles in diverse cellular processes and associate with a variety of cancers. DROSHA and DICER are two major enzymes in the miRNA maturation process. OBJECTIVE: Dicer and Drosha genes expression investigated Ovarian Cancer and analyzed the impact of clinicopathological characteristics on their expression. METHODS: The present study has performed on 50 cancer patients (50 tumor tissue samples and 50 marginal tissue samples) overall, 100 specimens referred to Al-Zahra Hospital's surgical department in Tabriz and Motahari Hospital Urmia for identification and treatment during 2018 and 2019. After extracting total RNA and cDNA Synthesis, using the HRM-PCR method, the rate of change in the expression of DROSHA and DICER genes assessed using the 2-ΔΔCT method. Data were analyzed using Paired t-test and Kolmogorov–Smirnov test. RESULTS: Our study showed a significant difference in the rate of expression changes in DROSHA and DICER genes in tumor tissue compared to marginal tissue. This difference was associated with an increase in DROSHA and DICER gene expression.CONCLUSIONS: Up-regulated expression of miRNAs biogenesis machinery enzymes (Dicer and Drosha) during ovarian cancer can alter the miRNA expression involved in the pathogenesis of malignancy.

scholarly journals Genomic profiling of Chinese patients with urothelial carcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bo Yang ◽  
Xiao Zhao ◽  
Chong Wan ◽  
Xin Ma ◽  
Shaoxi Niu ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Tumor Tissue ◽  
Genetic Alterations ◽  
Chinese Patients ◽  
Study Cohort ◽  
Genomic Feature ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Genomic Features ◽  
Somatic Alterations

Abstract Backgrounds Urothelial carcinoma (UC) is the most common genitourinary malignancy in China. In this study, we surveyed the genomic features in Chinese UC patients and investigated the concordance of genetic alterations between circulating tumor DNA (ctDNA) in plasma and matched tumor tissue. Materials and methods A total of 112 UC patients were enrolled, of which 31 were upper tract UC (UTUC) and 81 were UC of bladder (UCB). Genomic alterations in 92 selected genes were analyzed by targeted next-generation sequencing. Results In the study cohort, 94.64, 86.61 and 62.50% of patients were identified as having valid somatic, oncogenic and actionable somatic alterations, respectively. The most frequently altered genes included TP53, KMT2D, KDM6A, FAT4, FAT1, CREBBP and ARID1A. The higher prevalence of HRAS (22.0% vs 3.7%) and KMT2D (59.26% vs 34.57%) was identified in UTUC than in UCB. Comparisons of somatic alterations of UCB and UTUC between the study cohort and western cohorts revealed significant differences in mutant prevalence. Notably, 28.57, 17.86 and 47.32% of the cases harbored alterations in FGFRs, ERBBs and DNA damage repair genes, respectively. Furthermore, 75% of the patients carried non-benign germline variants, but only two (1.79%) were pathogenic. The overall concordance for genomic alterations in ctDNA and matched tumor tissue was 42.97% (0–100%). Notably, 47.25% of alterations detected in ctDNA were not detected in the matched tissue, and 54.14% of which were oncogenic mutations. Conclusions We found a unique genomic feature of Chinese UC patients. A reasonably good concordance of genomic features between ctDNA and tissue samples were identified.

scholarly journals Genomic Profiling of Chinese Urothelial Carcinoma Patients

2020 ◽  
Author(s):  
Bo Yang ◽  
Xiao Zhao ◽  
Chong Wan ◽  
Xin Ma ◽  
Shaoxi Niu ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Tumor Tissue ◽  
Genetic Alterations ◽  
Genomic Feature ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Genomic Features ◽  
Damage Repair ◽  
Somatic Alterations ◽  
Good Concordance

Abstract Background Urothelial carcinoma (UC) is the most common genitourinary malignancy in China. In this study, we studied the genomic features in Chinese UC patients, and investigated the concordance of genetic alterations between serum circulating tumor free DNA (ctDNA) and matched tumor tissue. Methods A total of 112 UC patients were enrolled, and 31 of which were upper tract UC (UTUC) and 81 were UC of bladder (UCB), respectively. Utilizing target next-generation sequencing, we analyzed genomic alterations of 92 selected genes. Results 94.64%, 86.61% and 62.50% of patients in our cohort were identified as having valid, oncogenic or actionable somatic alterations, respectively, and the most altered genes were TP53, KMT2D, KDM6A, FAT4, FAT1, CREBBP and ARID1A. HRAS (22.0% vs 3.7%) and KMT2D (59.26% vs 34.57%) were more altered in UTUC than in UCB in our cohort. Comparisons of somatic alterations of UCB and UTUC between our cohort and western cohorts revealed significant differences in gene prevalence. Notably, 28.57%, 17.86% and 47.32% of cases harbored alterations in FGFRs, ERBBs and DNA damage repair genes, respectively. Furthermore, 75% of patients carried non-benign germline variants, but only two (1.79%) were pathogenic. By comparison of ctDNA and matched tumor tissue, the overall concordance for genomic alterations was 42.97% (0-100%). 47.25% of alterations detected in ctDNA were not detected in the matched tissue, and 25.58% of which were oncogenic. Conclusions We found a unique genomic feature of Chinese UC patients. A good concordance of genomic features between ctDNA and tissue samples were identified.

scholarly journals Targeted Sequencing of Ascites and Peritoneal Washing Fluid of Patients With Gastrointestinal Cancers and Their Clinical Applications and Limitations

2021 ◽  
Vol 11 ◽  
Author(s):  
Go Eun Bae ◽  
Seok-Hwan Kim ◽  
Min Kyung Choi ◽  
Jin-Man Kim ◽  
Min-Kyung Yeo
Keyword(s):  
Tumor Tissue ◽  
Tumor Volume ◽  
Novel Mutation ◽  
Tumor Staging ◽  
Tissue Samples ◽  
Peritoneal Washing ◽  
Targeted Ngs ◽  
Gi Cancers ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Cytology from gastrointestinal (GI) cancers is frequently obtained from ascites and peritoneal washing fluids. Examination of ascites and peritoneal washing fluids from patients with GI cancers can help in the tumor staging and prognosis. Tumor-derived DNA in these cytology samples can be a target for next generation sequencing (NGS). Targeted NGS was evaluated in ascites and peritoneal washing samples obtained from 33 patients with GI cancers. These sequences were compared with those from tumor tissue samples, and correlated with cytopathologic findings of the ascites and peritoneal fluid samples. The correlation between fluid and tissue genotyping results was 25%, with a sensitivity of 21.43%. The volume of tumor contained within the fluid samples was low, ranging from ~0 to 10%. Importantly, the sensitivity of detection of somatic mutations in the fluid samples could be increased to 69.2% by assessing samples containing &gt;2% tumor volume. Evaluation of cells from ascitic fluid showed the presence of KRAS, TP53, and CDH1 mutations in 33, 13, and 7%, respectively, of patients with pancreatic cancer, and the presence of KRAS, TP53, and APC mutations in 25, 12, and 13%, respectively, of patients with gastric cancer. Ascites of one of the latter patients acquired KRAS mutation, which was a novel mutation during metastasis. Targeted NGS of ascites and peritoneal washing fluid have clinical implications, as well as limitations, in patients with GI cancers. NGS-based cytology examination may expand cytomolecular practices in GI cancer patients.

scholarly journals Pleomorphic Xanthoastrocytoma, Anaplastic Pleomorphic Xanthoastrocytoma, and Epithelioid Glioblastoma: Case Series With Clinical Characteristics, Molecular Features and Progression Relationship

2020 ◽  
Author(s):  
Zhiying Lin ◽  
Runwei Yang ◽  
Haojie Zheng ◽  
Zhiyong Li ◽  
Guozhong Yi ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Tumor Tissue ◽  
Case Series ◽  
Pleomorphic Xanthoastrocytoma ◽  
Braf V600e ◽  
Tissue Samples ◽  
Chromosome 1P ◽  
Molecular Features ◽  
Epithelioid Glioblastoma ◽  
Next Generation Sequencing Ngs

Abstract Background: Pleomorphic xanthoastrocytoma (PXA), anaplastic pleomorphic xanthoastrocytoma (A-PXA), and epithelioid glioblastoma (E-GBM) show overlapping features. However, little is known about their clinical characteristics, molecular features and progression relationship. Methods: Fourteen patients diagnosed at Nanfang Hospital from 2016 to 2019 were enrolled, including eleven PXA patients, two A-PXA patients, and one E-GBM patient. All tumor tissue samples of fourteen patients were examined by immunohistochemistry staining (MGMT, VEGF, BRAF-V600E, etc.). The recurred tumor tissue of the E-GBM patient arising from A-PXA was detected for 11 glioma markers (MGMT, BRAF-V600E, etc.) and chromosome 1p/19q by next generation sequencing (NGS). Results: The mean age of 13 patients with PXA or A-PXA was 25.4 years, twelve of whom were burdened with tumors at supratentorial regions. VEGF showed positive expression in the tumor samples of 13 patients, MGMT positive in 10 patients, and BRAF-V600E positive in 7 patients. As for the tumor sample of the E-GBM patient survived for up to 10 years after the fourth resections, BRAF V600E was wild-type in the sample obtained from the first surgery while it was mutant in the second, third, and fourth surgery. In the contrast, the promoter status of MGMT in four operations were unmethylated. The NGS results showed that the mutation frequencies of BRAF V600E in the second surgery, the third surgery and the fourth surgery were 14.06%, 9.13% and 48.29% respectively. Conclusions: Collectively, the results suggest that patients with A-PXA may relapse multiple times and eventually progress to E-GBM with BRAF-V600E mutation.

Comparison of somatic mutation profiles from cell free DNA (cfDNA) versus tissue in metastatic urothelial carcinoma (mUC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4533-4533 ◽  
Author(s):  
Michael L. Cheng ◽  
Maha Shady ◽  
Catharine Kline Cipolla ◽  
Samuel Funt ◽  
Maria E. Arcila ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Tumor Tissue ◽  
Intratumor Heterogeneity ◽  
Tumor Evolution ◽  
Bioinformatics Pipeline ◽  
Primary Tumors ◽  
Archival Tissue ◽  
Tissue Specimens ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data

4533 Background: Next-generation sequencing (NGS) of cfDNA is an emerging non-invasive strategy to define tumor mutation profiles that counters spatial and temporal limitations of sequencing single tissue specimens. We examined the feasibility of NGS of cfDNA in mUC and compared mutation profiles from cfDNA to results of tissue NGS previously performed in the clinical setting. Methods: Plasma cfDNA was collected in mUC pts and analyzed using a capture-based NGS assay (MSK-IMPACT) targeting 341-468 genes. NGS profiles from cfDNA and archival tumor tissue (using the same assay) were analyzed in parallel with an established bioinformatics pipeline to identify somatic variants. Results: In 26 pts, NGS analysis of cfDNA detected ≥1 somatic mutations (range 1-21) in 69% (18/26). For 15 pts, NGS data was available from archival tissue (11 primary tumors, 3 metastases, and matched primary/metastatic tissue in 1 case). The interval between cfDNA and tissue collection ranged from 35 days to > 4 yrs. 73% (11/15) of pts received intervening treatment, including 47% (7/15) with chemotherapy, 67% (10/15) with immunotherapy, and 40% (6/15) with both. In 40% (6/15), cfDNA harbored alterations not found in archival tumor tissue. In 73% (11/15), some mutations within archival tissue were not detected in cfDNA, including hotspot HER2 S310F and FGFR3 S249C mutations. Tumor and cfDNA mutation profiles were identical in 20% (3/15), with the tumor/cfDNA interval in this group ranging from 35 days to < 1.5 yrs. Somatic alterations including hotspot ERCC2 P463A and PIK3CA E545K mutations were detected in cfDNA from 3 pts where archival tumor tissue NGS failed. Thus, cfDNA identified new mutations in 50% (9/18) of pts for whom cfDNA identified somatic mutations and tissue NGS was previously attempted. Conclusions: NGS of cfDNA from mUC pts is feasible and successfully detected actionable alterations when archival tumor sequencing failed. The differences between tumor and cfDNA mutation profiles in many pts may reflect tumor evolution or intratumor heterogeneity. Mutation profiles in mUC may be incompletely assessed with NGS of archival tissue, and further investigation of plasma cfDNA for genomic profiling is warranted.

scholarly journals SAT-549 Identification of Somatic Mutations in CLCN2 as a Cause of Aldosterone-Producing Adenomas

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Juilee Rege ◽  
Kazutaka Nanba ◽  
Amy R Blinder ◽  
Tobias Else ◽  
Scott Tomlins ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Driver Mutations ◽  
Tissue Samples ◽  
Whole Exome ◽  
Formalin Fixed Paraffin ◽  
Targeted Ngs ◽  
Formalin Fixed Paraffin Embedded ◽  
Unilateral Disease ◽  
Next Generation Sequencing Ngs ◽  
Formalin Fixed

Abstract Background: Primary aldosteronism (PA) results from both unilateral and bilateral adrenal disease. Unilateral disease is most often caused by aldosterone-producing adenomas (APAs). We recently identified aldosterone-driver somatic mutations in approximately 90% of APAs using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided DNA sequencing approach. In the present study, we analyzed DNA from APA samples found to be mutation negative. Methods: Formalin-fixed paraffin-embedded tissue samples from PA patients who underwent adrenalectomy were studied. Genomic DNA was isolated from 118 APAs (identified by CYP11B2 IHC). Next generation sequencing (NGS) was performed to identify known aldosterone-driver mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D. APA DNA that was mutation negative and the adjacent normal adrenal tissue DNA were subjected to Whole Exome Sequencing (WES). Results: Targeted NGS and WES detected two variants in the voltage-gated chloride channel ClC-2 (encoded by CLCN2), which were confirmed by Sanger sequencing. One of the CLCN2 mutations (p.Gly24Asp) was identical to that previously found to cause germline early-onset PA. The second CLCN2 mutation, which would affect the same region of the protein, was an unreported PA mutation (p.Met22fs). The presence of these variants in two tumors suggests that CLCN2 mutations as a cause of APAs are rare with an approximate prevalence of 1.7% (2/118 APAs). Conclusion: In this study, we identified somatic mutations in CLCN2, in two of 118 APAs. Germline variants in this gene have previously been shown to cause of familial hyperaldosteronism type II and the current findings indicate that similar mutations cause a small proportion of APAs. These findings also indicate that WES of CYP11B2-guided mutation negative APAs can help determine rarer genetic causes of sporadic PA.

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