scholarly journals Genomic Profiling of Blood-Derived Circulating Tumor DNA from Patients with Advanced Biliary Tract Cancer

2021 ◽  
Vol 27 ◽  
Author(s):  
Chen Chen ◽  
Tao Wang ◽  
Mengmei Yang ◽  
Jia Song ◽  
Mengli Huang ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Circulating Tumor Dna ◽  
Chinese Patients ◽  
Ras Signaling ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Genomic Changes ◽  
Tract Cancer ◽  
Tumor Dna

Background: Biliary tract cancer is a highly lethal malignancy with poor clinical outcome. Accumulating evidence indicates targeted therapeutics may provide new hope for improving treatment response in BTC, hence better understanding the genomic profile is particularly important. Since tumor tissue may not be available for some patients, a complementary method is urgently needed. Circulating tumor DNA (ctDNA) provides a noninvasive means for detecting genomic alterations, and has been regarded as a promising tool to guide clinical therapies.Methods: Next-generation sequencing of 150 cancer-related genes was used to detect gene alterations in blood-derived ctDNA from 154 Chinese patients with BTC. Genomic alterations were analyzed and compared with an internal tissue genomic database and TCGA database.Results: 94.8% patients had at least one change detected in their ctDNA. The median maximum somatic allele frequency was 6.47% (ranging 0.1–34.8%). TP53 and KRAS were the most often mutated genes. The frequencies of single nucleotide variation in commonly mutated genes in ctDNA were similar to those detected in tissue samples, TP53 (35.1 vs. 40.4%) and KRAS (20.1 vs. 22.6%). Pathway analysis revealed that mutated genes were mapped to several key pathways including PI3K-Akt, p53, ErbB and Ras signaling pathway. In addition, patients harboring LRP1B, TP53, and ErbB family mutations presented significantly higher tumor mutation burden.Conclusions: These findings demonstrated that ctDNA testing by NGS was feasible in revealing genomic changes and could be a viable alternative to tissue biopsy in patients with metastatic BTC.

Blood-based genomic profiling of circulating tumor DNA from patients with advanced biliary tract cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1576-1576
Author(s):  
Junying Wang ◽  
Jia Song ◽  
Jing Zhao ◽  
Yuzi Zhang ◽  
Shangli Cai ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Tumor Heterogeneity ◽  
Circulating Tumor Dna ◽  
Pi3k Pathway ◽  
Chinese Patients ◽  
Tissue Samples ◽  
Tract Cancer ◽  
Tumor Dna

1576 Background: Biliary tract cancer (BTC) is a highly lethal malignancy as diagnosis occurring at late stages and marginally sensitive to chemotherapy. Increasing evidence indicates targeted therapeutics may provide new hope for improving clinical response in BTC, hence better comprehending the genomic profile is particularly important. However, tissue of BTC is highly wide tumor heterogeneity and often inadequate for molecular characterization, a proper method is urgently needed. Circulating tumor DNA (ctDNA) is an emerging technology for detecting actionable alterations, and may be regarded as a reliable tool to reveal genomic signature. Methods: Next-generation sequencing (NGS) targeted 150 cancer-related genes was used to detect blood-based ctDNA from 154 Chinese patients with BTC. The mean sequencing depth was more than 3000×. Somatic genomic alternations (GA) including single nucleotide variation (SNV), copy number variation (CNV) and fusion were analyzed and compared with an internal tissue genomic database (545 Chinese patients with BTC) tested by NGS and TCGA database (n = 227) tested by the whole exome sequencing (WES). Allele frequency (AF) represented the percentage of mutant allele reads relative to total allele reads (mutant plus wild type). Maximum somatic allele frequency (MSAF) was defined as the maximum AF (0.1% < AF < 35%) of all the somatic alterations identified per sample. Results: Among ctDNA database, at least one GA was found in 95% (147/154) of samples (a median of 4 GA per patient). The median MSAF across all cases was 6.47% (range, 0%-34.8%). Pathologic type (P < 0.001) and sex (P < 0.001) were significantly related with MSAF, respectively. Frequencies of SNV in commonly mutated genes from ctDNA were similar to those observed among tissue samples, like TP53 (35.1% vs 40.4%) and KRAS (20.1% vs 22.6%), however, a little lower in TCGA database (TP53 24.2%; KRAS 10.1%). Besides, the consistency of CNV detected from ctDNA and tissue was relatively poor, and tumor heterogeneity might be in charge of this phenomenon. Among the highly frequent mutations (AF > 5%) in ctDNA, 45% of genes was considered as druggable targets, such as EGFR/RAS/RAF pathway and AKT/mTOR/PI3K pathway. Conclusions: These findings demonstrated that ctDNA tested by NGS was feasible in revealing genomic profiles and identifying potential therapeutic targets. Noninvasive ctDNA could be used as a complementary approach to tissue testing in patients with metastatic BTC.

Genotyping of circulating tumor DNA in biliary tract cancer to reveal diagnostic and prognostic information.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 291-291 ◽  
Author(s):  
Andreas Wolfgang Berger ◽  
Thomas Jens Ettrich ◽  
Daniel Schwerdel ◽  
Anna Dolnik ◽  
Florian Beuter ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Palliative Treatment ◽  
Tumor Tissue ◽  
Locally Advanced ◽  
Circulating Tumor Dna ◽  
Imaging Data ◽  
Tract Cancer ◽  
Pretreated Patients ◽  
Tumor Dna

291 Background: Biliary tract cancer (BTC) shows increasing incidence and is associated with a high mortality. Diagnosis is difficult due to the frequently occurring inaccessibility of the tumor for biopsy. Noninvasive approaches for (i) assessing and (ii) monitoring the tumor-specific molecular setup are desirable. Characterization of circulating tumor DNA (ctDNA) may help to achieve this goal. Methods: Blood and tumor tissue samples from patients with locally advanced or metastatic BTC prior to and during palliative treatment were collected. Tumor tissue and corresponding ctDNA samples underwent targeted genotyping of the 15 most frequently mutated genes in BTC. Findings were correlated with clinical and imaging data. Results: 24 therapy naive patients with histologically confirmed BTC were included for analyses. The overall mutational concordance (blood/tissue) was 74% and 92% for intrahepatic tumors. The mean variant allele frequency (VAF) in tumor tissue of therapy naïve patients was significantly higher compared to the respective ctDNA (p = 0.0291). In turn, the sequencing depth for ctDNA was significantly deeper (p = 0.0001), enabling us to detect also rare variants. Mean ctDNA VAF at baseline significantly correlated with tumor load (Spearman, r = 0.4073, p = 0.0433) and, exclusively for intrahepatic tumors, also with progression-free survival (Spearman, r = -0.5878, p = 0.0386). During 1st line palliative treatment, we detected a change in the mutational landscape in 36% of cases, Moreover, we had access to ctDNA samples of 5 pretreated patients. While ctDNA samples of therapy naïve patients (n = 23) showed a mean of 0.78 mutations per patient, ctDNA samples of pretreated patients (n = 5) exhibited a mean of 0.4 mutations (p = 0.5519). Conclusions: The molecular landscape of BTC is depicted in ctDNA which may enable to adapt diagnostic and therapeutic strategies to the specific molecular setup present at a certain time. In contrast, the use of targeted resequencing is likely to be insufficient for a comprehensive assessment of treatment induced BTC evolution. For this purpose, we suggest a more extensive analysis of ctDNA by broader sequencing applications and the incorporation of epigenetics.

scholarly journals Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

2021 ◽  
Vol 9 (11) ◽  
pp. e003214
Author(s):  
Xiaofeng Chen ◽  
Deqiang Wang ◽  
Jing Liu ◽  
Jingrong Qiu ◽  
Jun Zhou ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Poor Prognosis ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Chinese Patients ◽  
Genomic Alterations ◽  
Early Stage Disease ◽  
Tract Cancer

BackgroundRecently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in biliary tract cancer (BTC), which includes gallbladder cancer (GBC) and cholangiocarcinoma (CHOL). Understanding the association between immunotherapy outcomes and the genomic profile of advanced BTC may further improve the clinical benefits from immunotherapy.MethodsGenomic tumor DNA was isolated from 98 Chinese patients with advanced BTC and used for targeted next-generation sequencing of 416 cancer-related genes to identify the genomic alterations common to advanced BTC. Thirty-four patients had received ICI camrelizumab plus gemcitabine and oxaliplatin (from the NCT03486678 trial) as a first-line treatment. Tumor-infiltrating immune cells were evaluated using immunofluorescence staining.ResultsKRAS and TP53 mutations were much more frequent in the advanced-stage BTC cohort than in other cohorts with mostly early stage disease. Specifically, KRAS-TP53 co-mutations were favored in advanced CHOL, with a favorable response to immunotherapy, while single KRAS mutations predicted poor prognosis and immunotherapy outcomes for CHOL. Compared with GBC, CHOL had more mutations in genes involved in KRAS signaling; a high mutation load in these genes correlated with poor immunotherapy outcomes and may subsequently cause inferior immunotherapy outcomes for CHOL relative to GBC. Furthermore, a genomic signature including 11 genes was developed; their mutated subtype was associated with poor prognosis and immunotherapy outcomes in both CHOL and GBC. Transcriptome analyses suggested immune dysfunction in the signature mutated subtype, which was validated by tumor microenvironment (TME) evaluation based on detection of immune cell infiltration. Importantly, the signature wild-type subtype with favorable TME may be an advantageous population of immunotherapy.ConclusionsGenomic alterations in advanced BTC were associated with specific prognosis and immunotherapy outcomes. Combining genomic classification with TME evaluation further improved the stratification of immunotherapy outcomes.

Genotyping of circulating tumor DNA in biliary tract cancer reveals diagnostic and prognostic information.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e16147-e16147 ◽  
Author(s):  
Andreas Wolfgang Berger ◽  
Thomas Jens Ettrich ◽  
Daniel Schwerdel ◽  
Anna Dolnik ◽  
Florian Beuter ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Circulating Tumor Dna ◽  
Prognostic Information ◽  
Tract Cancer ◽  
Tumor Dna

scholarly journals Concordance of Genomic Alterations between Circulating Tumor DNA and Matched Tumor Tissue in Chinese Patients with Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Bing Xu ◽  
Guangyu Shan ◽  
Qixi Wu ◽  
Weiwei Li ◽  
Hongjiang Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Circulating Tumor Dna ◽  
Concordance Rate ◽  
Chinese Patients ◽  
Genomic Alteration ◽  
Single Nucleotide Variants ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Wilcoxon Rank Sum Test ◽  
Tumor Dna

Purpose. Circulating tumor DNA (ctDNA) served as a noninvasive method with less side effects using peripheral blood. Given the studies on concordance rate between liquid and solid biopsies in Chinese breast cancer (BC) patients were limited, we sought to examine the concordance rate of different kinds of genomic alterations between paired tissue biopsies and ctDNA samples in Chinese BC cohorts. Materials and Methods. In this study, we analyzed the genomic alteration profiles of 81 solid BC samples and 41 liquid BC samples. The concordance across 136 genes was evaluated. Results. The median mutation counts per sample in 41 ctDNA samples was higher than the median in 81 tissue samples (p=0.0254; Wilcoxon rank sum test). For mutation at the protein-coding level, 39.0% (16/41) samples had at least one concordant mutation in two biopsies. 20.0% tissue-derived mutations could be detected via ctDNA-based sequencing, whereas 11.7% ctDNA-derived mutations could be found in paired tissues. At gene amplification level, the overall concordant rate was 68.3% (28/41). The concordant rate at gene level for each patient ranged from 83.8% (114/136) to 99.3% (135/136). And, the mean level of variant allele frequency (VAF) for concordant mutations in ctDNA was statistically higher than that for the discordant ones (p<0.001; Wilcoxon rank sum test). Across five representative genes, the overall sensitivity and specificity were 49.0% and 85.9%, respectively. Conclusion. Our results indicated that ctDNA could provide complementary information on genetic characterizations in detecting single nucleotide variants (SNVs) and insertions and deletions (InDels).

scholarly journals Circulating Tumor DNA in Biliary Tract Cancer: Current Evidence and Future Perspectives

2020 ◽  
Vol 17 (5) ◽  
pp. 441-452 ◽  
Author(s):  
ALESSANDRO RIZZO ◽  
ANGELA DALIA RICCI ◽  
SIMONA TAVOLARI ◽  
GIOVANNI BRANDI
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Circulating Tumor Dna ◽  
Current Evidence ◽  
Future Perspectives ◽  
Tract Cancer ◽  
Tumor Dna

scholarly journals Genotyping of circulating tumor DNA in biliary tract cancer reveals diagnostic and prognostic information

2018 ◽  
Vol 29 ◽  
pp. viii660
Author(s):  
T.J. Ettrich ◽  
D. Schwerdel ◽  
A. Dolnik ◽  
F. Beuter ◽  
T. Blätte ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Circulating Tumor Dna ◽  
Prognostic Information ◽  
Tract Cancer ◽  
Tumor Dna

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.

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