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 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 PATH-06. ASSESSMENT OF CIRCULATING TUMOR DNA IN CEREBROSPINAL FLUID BY WHOLE EXOME SEQUENCING TO DETECT GENOMIC ALTERATIONS OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii165-ii165
Author(s):  
Hao Duan ◽  
Zhenqiang He ◽  
Zhenghe Chen ◽  
Yonggao Mou
Keyword(s):  
Cerebrospinal Fluid ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Tumor Tissue ◽  
Circulating Tumor Dna ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Whole Exome ◽  
Resected Tumor ◽  
Tumor Dna

Abstract Cerebrospinal fluid (CSF) has been demonstrated as a better source of circulating tumor DNA (ctDNA) than plasma for brain tumors. However, it is unclear whether whole exome sequencing (WES) is qualified for detection of ctDNA in CSF. The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma. CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery, Sun Yat-sen University Cancer Center. ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES. The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared. Due to the ctDNA in CSF was unqualified for exome sequencing for one patient, nine patients were included into the final analysis. More glioblastoma-associated mutations tended to be detected in CSF comparing with the corresponding tumor tissue samples (3.56±0.75 vs. 2.22±0.32, P=0.097), while the statistical significance was limited by the small sample size. The average mutation frequencies were similar in CSF and tumor tissue samples (74.12% ± 6.03% vs. 73.83% ± 5.95%, P = 0.924). The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3F3A which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES. Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF. Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma, which may provide useful information for the decision of treatment strategy.

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]

Spectrum of FGFR2/3 Alterations in Cell-Free DNA of Patients with Advanced Urothelial Carcinoma

2021 ◽  
pp. 1-6
Author(s):  
Petros Grivas ◽  
Lesli A. Kiedrowski ◽  
Guru P. Sonpavde ◽  
Sumati V. Gupta ◽  
Roby A. Thomas ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Targeted Therapies ◽  
Detection Rate ◽  
Tumor Tissue ◽  
Treatment Options ◽  
Genomic Alterations ◽  
Free Dna ◽  
Activating Mutation ◽  
Platinum Refractory ◽  
Advanced Urothelial Carcinoma

Detecting genomic alterations (GAs) in advanced urothelial carcinoma (aUC) can expand treatment options by identifying candidates for targeted therapies. Erdafitinib is FDA-approved for patients with platinum-refractory aUC with activating mutation or fusion in FGFR2/3. We explored the prevalence and spectrum of FGFR2/3 GAs identified with plasma cfDNA NGS testing (Guardant360) in 997 patients with aUC. FGFR2/3 GAs were detected in 201 patients (20%) with characterized activating GAs in 141 (14%). Our results indicate the Guardant360-based FGFR2/3 GA detection rate is similar to those described from previous studies employing tumor tissue testing, suggesting that plasma-based cfDNA NGS may non-invasively identify candidates for anti-FGFR targeted therapies.

Genomic alterations in upper tract urothelial carcinoma (UTUC) versus urothelial carcinoma of the bladder (UBC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 431-431
Author(s):  
Stephanie A. Mullane ◽  
Guillermo de Velasco ◽  
Toni K. Choueiri ◽  
Philip W. Kantoff ◽  
Joaquim Bellmunt
Keyword(s):  
Urothelial Carcinoma ◽  
Somatic Mutations ◽  
Tumor Stage ◽  
Copy Number Alterations ◽  
Sequencing Data ◽  
Genomic Alterations ◽  
Biologically Relevant ◽  
Somatic Alterations ◽  
Tumor Sequencing ◽  
Carcinoma Of The Bladder

431 Background: Defining the landscape of genomic alterations in UTUC as well as identifying the genomic differences from UBC, may provide insights into the treatment of UTUC. Methods: We interrogated our enterprise-wide institutional targeted next generation tumor sequencing data to compare genomic alterations in patients with UTUC (n = 25) with UBC (n = 72), irrespective of tumor stage. We described differences in frequencies of somatic mutations and copy number alterations in 300 relevant cancer-associated genes. Results: UTUC and UBC demonstrated differences in somatic alterations. Genes more commonly found in UTUC included FGFR3 (20% v. 7.5%), STAG2 (16% v. 7.5%), RB1 (24% v. 16%), TSC1 (16% v. 5.4%), EP300 (12% v. 5.4%), IGFIR (20% v. 0%), and Notch1 (24% v. 0%) (see table). Alterations in FGFR3 and TP53 co-existed in only on patient. We did identify two UTUC patients with MSH2 alterations, both of whom had previously been diagnosed with Lynch Syndrome. Conclusions: Biologically relevant differences exist between UTUC and UBC. We observed an enrichment of potentially targetable mutations including TSC1 and FGFR3. Findings in the genomic profile underline the need to consider these two locations as unique entities for future biologically driven trials. [Table: see text]

Genomic characteristics associated with clinical activity of rucaparib in patients (pts) with BRCA1 or BRCA2 (BRCA)-mutated metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 178-178 ◽  
Author(s):  
Wassim Abida ◽  
David Campbell ◽  
Akash Patnaik ◽  
Brieuc Sautois ◽  
Jeremy David Shapiro ◽  
...  
Keyword(s):  
Parp Inhibitor ◽  
Objective Response ◽  
Response Rates ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Tissue Samples ◽  
Damage Repair ◽  
Measurable Disease ◽  
Psa Response ◽  
Somatic Alterations

178 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in pts with mCRPC and a deleterious germline or somatic alteration in BRCA ( BRCA pts) or 1 of 13 other DNA damage repair (DDR) genes. Methods: Eligible pts had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy. Deleterious DDR gene alterations were identified from central testing of plasma and/or tissue samples by Foundation Medicine or from local testing. Results: As of Jul 2, 2019 (visit cutoff), 98 BRCA pts had received rucaparib; median (range) duration of follow-up was 13.0 (4.1–25.8) mo. Confirmed objective response rate (ORR) in BRCA pts (with investigator-assessed measurable disease) and PSA response rates (in pts with and without measurable disease) are shown in the Table. A biallelic alteration was observed in 81.4% (35/43) of BRCA pts for whom zygosity could be determined, and pts with homozygous BRCA loss (20.4%; 20/98) demonstrated high ORR (66.7% [95% CI, 38.4-88.2]; 10/15) and PSA response rates (75.0% [95% CI, 50.9-91.3]; 15/20). The safety profile in BRCA pts was consistent with the overall TRITON2 pt population. Conclusions: Results from TRITON2 showed antitumor activity with rucaparib in pts with mCRPC and a deleterious BRCA alteration. Responses were observed in patients with germline or somatic alterations in BRCA1 or BRCA2. The activity of rucaparib in these and additional genomic subgroups (e.g., based on zygosity, plasma genomic testing, or co-occurring alterations) will be reported. Clinical trial information: NCT02952534. [Table: see text]

scholarly journals Blood-Based Liquid Biopsy for Comprehensive Cancer Genomic Profiling Using Next-Generation Sequencing: An Emerging Paradigm for Non-invasive Cancer Detection and Management in Dogs

2021 ◽  
Vol 8 ◽  
Author(s):  
Kristina M. Kruglyak ◽  
Jason Chibuk ◽  
Lisa McLennan ◽  
Prachi Nakashe ◽  
Gilberto E. Hernandez ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Liquid Biopsy ◽  
Tumor Tissue ◽  
Genomic Profiling ◽  
Next Generation ◽  
Blood Draw ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Non Invasive ◽  
Generation Sequencing

This proof-of-concept study demonstrates that blood-based liquid biopsy using next generation sequencing of cell-free DNA can non-invasively detect multiple classes of genomic alterations in dogs with cancer, including alterations that originate from spatially separated tumor sites. Eleven dogs with a variety of confirmed cancer diagnoses (including localized and disseminated disease) who were scheduled for surgical resection, and five presumably cancer-free dogs, were enrolled. Blood was collected from each subject, and multiple spatially separated tumor tissue samples were collected during surgery from 9 of the cancer subjects. All samples were analyzed using an advanced prototype of a novel liquid biopsy test designed to non-invasively interrogate multiple classes of genomic alterations for the detection, characterization, and management of cancer in dogs. In five of the nine cancer patients with matched tumor and plasma samples, pre-surgical liquid biopsy testing identified genomic alterations, including single nucleotide variants and copy number variants, that matched alterations independently detected in corresponding tumor tissue samples. Importantly, the pre-surgical liquid biopsy test detected alterations observed in spatially separated tissue samples from the same subject, demonstrating the potential of blood-based testing for comprehensive genomic profiling of heterogeneous tumors. Among the three patients with post-surgical blood samples, genomic alterations remained detectable in one patient with incomplete tumor resection, suggesting utility for non-invasive detection of minimal residual disease following curative-intent treatment. Liquid biopsy allows for non-invasive profiling of cancer-associated genomic alterations with a simple blood draw and has potential to overcome the limitations of tissue-based testing posed by tissue-level genomic heterogeneity.

scholarly journals The Clinical Implications of Tumor Mutational Burden in Osteosarcoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Lu Xie ◽  
Yufei Yang ◽  
Wei Guo ◽  
Dongxue Che ◽  
Jie Xu ◽  
...  
Keyword(s):  
Cox Regression ◽  
White Blood Cells ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Tissue Samples ◽  
Mutational Burden ◽  
Kaplan Meier ◽  
Whole Exome ◽  
Tumor Mutational Burden ◽  
Somatic Alterations

BackgroundOsteosarcoma (OTS) is aggressive bone malignancy without well-recognized prognosis biomarker. Tumor mutational burden (TMB) has been proved as effective biomarker in predicting clinical outcomes in several cancer types. However, its prognostic value in OTS remains unknown. In this study, we aim to evaluate the implication of TMB in OTS patients.MethodsTo depict the landscape of somatic mutations in OTS, we performed Whole-Exome Sequencing (WES) on 31 OTS tissue samples and corresponding White Blood Cells (WBCs) as matched control. TMB was calculated as the total number of somatic alterations in coding regions normalized to the per sequenced genomic megabase (~30.4Mb in WES). The prognostic values of TMB were evaluated by Kaplan-Meier methods and Cox regression models.ResultsThe median age was 16.0 years at diagnosis, and 54.8% of patients were male. The most common genetic alterations were mainly involved in cell cycle and DNA damage response and repair, including H3F3A, TP53, MYC, and CDKN2A/B. The median progression-free survival (PFS) was 775.5 days in TMB-High (defined as third quartile of TMB value, <2.565) versus 351 days in TMB-Low (<2.565). All patients with TMB-High are PFS-Long (>400 days), while 36.4% of all patients with TMB-Low were PFS-Long (P=0.003). TMB were significantly greater in PFS-Long than in PFS-Short (<400 days) (P=0.002). Moreover, the median overall survival (OS) was 1,307 days in TMB-High versus 672.5 days in TMB-Low. Furthermore, TMB-High group had significantly improved PFS (P=0.04) and OS (P=0.03).ConclusionsTMB-High can be used as prognostic marker for OTS. Our findings demonstrate that TMB may be helpful in combination with traditionally clinicopathologic risk factors to optimize risk stratification and guide treatment decisions.

Characteristics of genomic alterations in circulating tumor DNA (ctDNA) in patients (Pts) with advanced gastrointestinal (GI) cancers in nationwide large-scale ctDNA screening:SCRUM-Japan Monstar-Screen.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 106-106
Author(s):  
Yoshiaki Nakamura ◽  
Takao Fujisawa ◽  
Shigenori Kadowaki ◽  
Naoki Takahashi ◽  
Masahiro Goto ◽  
...  
Keyword(s):  
Large Scale ◽  
Tumor Tissue ◽  
Circulating Tumor Dna ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Gi Cancer ◽  
Oncogenic Pathways ◽  
Treatment Naïve ◽  
Gi Cancers ◽  
Ctdna Analysis

106 Background: Analysis of ctDNA has been utilized in pts with advanced GI cancer for identification of genomic alterations for targeted therapy. However, the characteristics of ctDNA genomic alterations of GI cancers compared to non-GI cancers remains unclear. Methods: Pts with advanced solid tumors were eligible in MONSTAR-SCREEN, a nationwide ctDNA screening project in Japan. Plasma samples were analyzed by an NGS-based 70-gene ctDNA assay, FoundationOne Liquid (F1L) at a CLIA-certified and CAP-accredited laboratory since Jul 2019. For treatment-naïve pts, tumor tissue samples were analyzed by FoundationOne CDx (F1CDx), a 324-gene tissue-based panel. Results: As of Jun 18 2020, out of enrolled 540 pts with advanced solid tumor, 470 pts, consisting of 133 with advanced GI cancers (67 colorectal, 48 gastric, 14 esophageal, 2 gastrointestinal tumor (GIST) and 2 small intestinal) and 337 non-GI cancers (103 hepatobiliary and pancreatic, 70 genitourinary, 64 breast, 46 head and neck, 33 gynecologic, and 21 skin), had an available ctDNA result. Sequencing success rate was similar between GI and non-GI cancers (91.7% vs. 89.3%, P = 0.50). GI cancers had a significantly higher ctDNA level (maximum variant allele fraction) than non-GI cancers (median, 11.8% vs. 0.57%; P = 1.6E-7). The most frequently altered genes were TP53 (73%), APC (73%), KRAS (30%), BRAF (15%), and PIK3CA (12%) in colorectal cancer, TP53 (44%), KRAS (19%), PIK3CA (15%), ATM (10%), and ERBB2 (10%) in gastric cancer, and TP53 (79%), ATM (21%), ERBB2 (21%) in esophageal cancer. Mutations in genes in pathways related to RAS/RAF/MEK (39.1 % vs. 21.4 %, P = 1.8E-4), receptor tyrosine kinase (20.3% vs 11.9%, P = 0.027), p53 (66.2% vs 49.6%, P = 0.0014), and Wnt (41.4% vs 4.7%, P = 4.4E-21) were significantly enriched in GI cancers compared to non-GI cancers. Tumor tissue samples were analyzed using F1CDx for 63 treatment-naïve pts, in which 51 (31.3%) of 132 alterations identified by F1L were not detected by F1CDx. Conclusions: GI cancers had higher ctDNA levels and distinct characteristics of ctDNA genomic alterations from non-GI cancers with an enrichment in several oncogenic pathways. One-third of ctDNA alterations were detected in only ctDNA, indicating the potential of ctDNA analysis to identify heterogenous genomic alterations in advanced GI cancer. Clinical trial information: UMIN000036749.

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