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 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 genomic landscape in Chinese patients with urothelial carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17009-e17009
Author(s):  
Haige Chen ◽  
Ruiyun Zhang ◽  
Shiqing Chen ◽  
Yuezong Bai
Keyword(s):  
Urothelial Carcinoma ◽  
Large Scale ◽  
Clinical Laboratory ◽  
Genomic Analysis ◽  
Chinese Patients ◽  
Variants Of Unknown Significance ◽  
Molecular Features ◽  
Genomic Landscape ◽  
Ffpe Tumor ◽  
Somatic Alterations

e17009 Background: Recent therapeutic advances, such as immunotherapy and FGFR-targeted therapy, have greatly improved the prognosis of patients with urothelial carcinoma (UC). Revealing comprehensive genomic features could evolve our understanding of UC, however the genomic landscape in Chinese UC has not been fully elucidated. In the present study, we investigated the molecular features of Chinese UC patients. Methods: Genomic profiling was performed through next generation sequencing (NGS) from Chinese patients with UC between January, 2017 and November, 2019 in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab. DNA was extracted from formalin fixed paraffin-embedded (FFPE) tumor specimens or fresh tumor tissue. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay or Ventana PD-L1 SP263 assay. Data analyses were performed using SPSS and R 3.6.1. Results: A total of 298 Chinese UC patients who have undergone NGS were included in this study, including 210 (70.5%) male and 88 (29.5%) female patients. The median age was 66 (range, 19-91) years old. The most common somatic alterations were detected in TP53 (57.0%), KMT2D (42.6%), TERT (28.2%), KDM6A (26.5%) and PIK3CA (18.8%). Of the 243 patients who were evaluated for PD-L1 expression, 78 (32.1%) had a PD-L1 Tumor Proportion Score (TPS) of 1% or greater, and 18 (7.4%) had a PD-L1 TPS of 50% or greater. The median TMB value was 9.7 muts/Mb (range: 0-175.0). 138 (46.3%) patients harbored alterations in DNA damage repair (DDR) genes, including pathogenic or likely pathogenic mutations (MUT) and variants of unknown significance (VOUS). The most common somatic alterations in DDR genes were detected in ATM (9.4%), BRCA2 (9.4%), BRIP1 (5.0%), ATR (4.7%) and BRCA1 (4.7%). Significant differences of TMB were observed among DDR-MUT group, DDR-VOUS group and DDR-WT group (mTMB = 16.1, 14.0 and 7.3 muts/Mb, respectively, P < 0.001). Seven (2.4%) patients were identified as MSI-H, including five patients in DDR-MUT group (12.8%) and two patients in DDR-VOUS group (2.0%). Conclusions: This is the first large-scale comprehensive genomic analysis for Chinese patients with UC. These results provide a better understanding of molecular features in Chinese UC patients which may lead to an improvement in the personalized treatment for these patients.

scholarly journals Mutational Spectrum Analysis of Seven Genes Associated with Thyroid Dyshormonogenesis

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Xi Chen ◽  
Xiaohong Kong ◽  
Jie Zhu ◽  
Tingting Zhang ◽  
Yanwei Li ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Genetic Alterations ◽  
Chinese Patients ◽  
Study Cohort ◽  
Chinese Han ◽  
Hormone Synthesis ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Thyroid Dyshormonogenesis ◽  
Generation Sequencing

Objective. Thyroid dyshormonogenesis (DH) is a genetically heterogeneous inherited disorder caused by thyroid hormone synthesis abnormalities. This study aims at comprehensively characterizing the mutation spectrum in Chinese patients with DH. Subjects and Methods. We utilized next-generation sequencing to screen for mutations in seven DH-associated genes (TPO, DUOX2, TG, DUOXA2, SLC26A4, SLC5A5, and IYD) in 21 Chinese Han patients with DH from Xinjiang Province. Results. Twenty-eight rare nonpolymorphic variants were found in 19 patients (90.5%), including 19, 5, 3, and 1 variants in DUOX2, TG, DUOXA2, and SLC26A4, respectively. Thirteen (62%) patients carried monogenic mutations, and six (28.5%) carried oligogenic mutations. Fifteen (71%) patients carried 2 or more DUOX2 (14) or DUOXA2 (1) variants. The genetic basis of DH in nine (43%) patients harboring biallelic or triallelic pathogenic variants was resolved. Seventeen patients (81%) carried DUOX2 mutations, most commonly p.R1110Q or p.K530X. No correlations were found between DUOX2 mutation types or numbers and clinical phenotypes. Conclusions. DUOX2 mutations were the most predominant genetic alterations of DH in the study cohort. Oligogenicity may explain the genetic basis of disease in many DH patients. Functional studies and further clinical studies with larger DH patient cohorts are needed to validate the roles of the mutations identified in this study.

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]

Comprehensive genomic profiling in Chinese patients with lung squamous cell carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8540-8540
Author(s):  
Zuping Lian ◽  
Heng Li ◽  
Youming Lei ◽  
Lei Xian ◽  
Kunpeng Bu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Copy Number Variations ◽  
Chinese Patients ◽  
Mutation Rates ◽  
Genomic Alteration ◽  
Genomic Alterations ◽  
Genomic Features

8540 Background: Lung squamous cell carcinoma (LUSC) is a major histological subtype of non-small cell lung cancer (NSCLC) and accounts for 30% of NSCLC. Previous studies had revealed the genomic characterization of LUSC in Western patients (pts). However, the comprehensive genomic features of LUSC in Chinese pts have not been well understood. Methods: Deep sequencing targeting 450 cancer genes was performed on FFPE and matching blood samples collected from 311 LUSC pts. Genomic alterations (GAs) including single nucleotide variations, short and long insertions and deletions, copy number variations, and gene rearrangements were analyzed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. Results: The median age of LUSC pts was 63 years old (range 57-68.5), of which 88% were male. The most frequently mutated genes were TP53 (88%), PIK3CA (34%), CDKN2A (33%), SOX2 (26%), LRP1B (22%), KLHL6 (21%), KMT2D (19%), PRKCI (19%), NFE2L2 (18%) and MAP3K13 (17%). Interestingly the mutation rates of PIK3CA (p = 1.93e-05) and CDKN2A (p = 2.48e-05) were significantly higher than that in TCGA cohort. Genomic alterations in eight druggable genes recommended by the NCCN guideline occurred in 32% of pts, and alterations to PI3K/mTOR signaling pathway related genes occurred in 52% of pts. One patient with PIK3CA amplification achieved stable disease for eight months after everolimus treatment. Moreover, variants in the homologous recombination (HR) pathway were identified in 17% of pts. The median TMB of LUSC pts was 10.8 Muts/MB (range 6.9-14.5 Muts/MB) which was higher than Western populations [PMID: 28420421]. The 1st Quartile (TMB-L), median and 3rd Quartile (TMB-H) TMB value was 6.9, 10.8 and 14.5 Muts/Mb respectively. Comparing with the TMB-L group, frequencies of CDKN2A (39% vs 19%, p= 0.005), LRP1B (45% vs 8%, p< 0.001) and KMT2D (27% vs 8%, p= 0.002) were higher in TMB-H group. Conclusions: In summary, we characterized the genomic alteration profile of Chinese LUSC pts. Consistent with previous reports, high mutation rates of TP53, PIK3CA and CDKN2A are the most important genomic features of LUSC. However, the proportion of PIK3CA and CDKN2A mutations in Chinese LUSC pts is higher than that of Western populations. In addition, we also found targetable pathways (including PI3K/mTOR) along with gene related variations and high TMB in many pts, providing potential targeted therapy and immunotherapy options for LUSC pts.

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.

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