scholarly journals Combining tissue and circulating tumor DNA increases the detection rate of a CTNNB1 mutation in hepatocellular carcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Stine Karlsen Oversoe ◽  
Michelle Simone Clement ◽  
Britta Weber ◽  
Henning Grønbæk ◽  
Stephen Jacques Hamilton-Dutoit ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mutation Rate ◽  
Detection Rate ◽  
Tumor Tissue ◽  
Circulating Tumor Dna ◽  
Treatment Modalities ◽  
Advanced Hepatocellular Carcinoma ◽  
Tissue Samples ◽  
The Impact ◽  
Tumor Dna

Abstract Background and aims Studies suggest that mutations in the CTNNB1 gene are predictive of response to immunotherapy, an emerging therapy for advanced hepatocellular carcinoma (HCC). Analysis of circulating tumor DNA (ctDNA) offers the possibility of serial non-invasive mutational profiling of tumors. Combining tumor tissue and ctDNA analysis may increase the detection rate of mutations. This study aimed to evaluate the frequency of the CTNNB1 p.T41A mutation in ctDNA and tumor samples from HCC patients and to evaluate the concordance rates between plasma and tissue. We further evaluated changes in ctDNA after various HCC treatment modalities and the impact of the CTNNB1 p.T41A mutation on the clinical course of HCC. Methods We used droplet digital PCR to analyze plasma from 95 patients and the corresponding tumor samples from 37 patients during 3 years follow up. Results In tumor tissue samples, the mutation rate was 8.1% (3/37). In ctDNA from HCC patients, the CTNNB1 mutation rate was 9.5% (9/95) in the pre-treatment samples. Adding results from plasma analysis to the subgroup of patients with available tissue samples, the mutation detection rate increased to 13.5% (5/37). There was no difference in overall survival according to CTNNB1 mutational status. Serial testing of ctDNA suggested a possible clonal evolution of HCC or arising multicentric tumors with separate genetic profiles in individual patients. Conclusion Combining analysis of ctDNA and tumor tissue increased the detection rate of CTNNB1 mutation in HCC patients. A liquid biopsy approach may be useful in a tailored therapy of HCC.

scholarly journals Combining Tissue and Circulating Tumor DNA Increases the Detection Rate of CTNNB1 Mutation in Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Stine Karlsen Oversoe ◽  
Michelle Simone Clement ◽  
Britta Weber ◽  
Henning Grønbæk ◽  
Stephen Jacques Hamilton-Dutoit ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mutation Rate ◽  
Detection Rate ◽  
Tumor Tissue ◽  
Circulating Tumor Dna ◽  
Treatment Modalities ◽  
Advanced Hepatocellular Carcinoma ◽  
Tissue Samples ◽  
The Impact ◽  
Tumor Dna

Abstract Background and aims: Studies suggest that mutations in the CTNNB1 gene are predictive of response to immunotherapy, an emerging therapy for advanced hepatocellular carcinoma (HCC). Analysis of circulating tumor DNA (ctDNA) offers the possibility of serial non-invasive mutational profiling of tumors. Combining tumor tissue and ctDNA analysis may increase the detection rate of mutations.This study aimed to evaluate the frequency of the CTNNB1 p.T41A mutation in ctDNA and tumor samples from HCC patients and to evaluate the concordance rates between plasma and tissue. We further evaluated changes in ctDNA after various HCC treatment modalities and the impact of the CTNNB1 p.T41A mutation on the clinical course of HCC.Methods: We used droplet digital PCR to analyze plasma from 95 patients and the corresponding tumor samples from 37 patients during three years of follow up. Results: In tumor tissue samples, the mutation rate was 8.1% (3/37). In ctDNA from HCC patients, we found a CTNNB1 mutation rate of 9.5% (9/95) in the pre-treatment samples. Adding results from plasma analysis to the subgroup of patients with available tissue samples, the mutation detection rate increased to 13.5% (5/37). There was no difference in overall survival according to CTNNB1 mutational status. Serial testing of ctDNA indicated a clonal evolution of HCC or arising of multicentric tumors with separate genetic profiles.Conclusion: Combining analysis of ctDNA and tumor tissue increased the detection rate of CTNNB1 mutation in HCC patients. A liquid biopsy approach may be useful in a tailored therapy of HCC.

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.

Mutations in circulating tumor DNA predict primary resistance to systemic therapies in patients with advanced hepatocellular carcinoma

2020 ◽  
Vol 73 ◽  
pp. S900
Author(s):  
Johann von Felden ◽  
Amanda J. Craig ◽  
Ismail Labgaa ◽  
Teresa Garcia-Lezana ◽  
Delia D’Avola ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Circulating Tumor Dna ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Tumor Dna ◽  
Systemic Therapies

Utilizing phenotypic characteristics of metastatic brain tumors to predict the probability of circulating tumor DNA detection from cerebrospinal fluid.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2507-2507
Author(s):  
Meichen Li ◽  
Delan Li ◽  
Xue Hou ◽  
Xiangheng Zhang ◽  
Na Wang ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Metastases ◽  
Detection Rate ◽  
Cross Validation ◽  
Lesion Size ◽  
Circulating Tumor Dna ◽  
Intracranial Lesion ◽  
Shortest Distance ◽  
The Impact ◽  
Tumor Dna

2507 Background: Brain metastases occur in approximately 20% of tumor patients and is often associated with terminal events and poor prognosis. Cerebrospinal fluid (CSF) can be a promising source for detecting circulating tumor DNA (ctDNA) specific to the central nervous system (CNS) instead of peripheral blood due to the blood-brain barrier. However, CSF’s suboptimal ctDNA detection rate might limit its clinical application. Precise screening of suitable patients is needed to maximize clinical benefit. Methods: We sequenced 425 cancer-relevant genes in CSF and matched extracranial tissue or blood samples obtained from 67 lung cancer patients with brain metastases. The impact of clinical factors, including age, gender, tumor size, number of lesions, and distance of lesions to the ventricle on CSF ctDNA detection was then evaluated by univariate logistic regression. To predict the probability of successful CSF ctDNA detection, best subsets regression was employed for feature selection and cross validation was used for performance assessment to determine the final model. Results: We detected somatic alterations in 39/67 (58%) CSF ctDNA, 57/66 (86%) plasma ctDNA and 45/49 (92%) tissue samples. Mutation detection rate of CSF ctDNA was significantly lower than that from extracranial tissue and plasma (P < 0.001). Univariate analysis revealed significant association (P < 0.05) of high CSF ctDNA detection rate with the following features: (1) intracranial lesion size ( T), (2) shortest distance between the largest lesion and the ventricle ( Dtop), and (3) shortest distance between all intracranial lesion and the ventricle ( Dall). We also revealed a trend of higher detection rate in patients with CNS symptoms ( SCNS). Subsequent best subsets analysis and cross validation suggested best prediction power with lesion size and largest lesion-ventriclar distance (area under curve [AUC], 0.76 [95% CI, 0.71 to 0.85]; accuracy, 0.75 [95% CI, 0.70 to 0.81]). Final probability can then be derived from Logit P = 0.11×T−0.16×Dall (AUC, 0.82; sensitivity, 0.91; specificity, 0.74). The detection of CSF ctDNA was significantly improved from 58% to 83% (P = 0.03) based on the model. Conclusions: This study established a regression model to predict the probability of CSF ctDNA that can be useful to facilitate clinical decisions and avoid excessive practice when monitoring tumor evolution in the brain.

scholarly journals Next‐Generation Sequencing of Circulating Tumor DNA Reveals Frequent Alterations in Advanced Hepatocellular Carcinoma

2018 ◽  
Vol 23 (5) ◽  
pp. 586-593 ◽  
Author(s):  
Sadakatsu Ikeda ◽  
Igor F. Tsigelny ◽  
Åge A. Skjevik ◽  
Yuko Kono ◽  
Michel Mendler ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Next Generation Sequencing ◽  
Circulating Tumor Dna ◽  
Advanced Hepatocellular Carcinoma ◽  
Next Generation ◽  
Tumor Dna ◽  
Generation Sequencing

Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced hepatocellular carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15606-e15606
Author(s):  
Mao Li ◽  
Ailin Wei ◽  
Wenzhuan Xie ◽  
Jing Zhao ◽  
Zhengyi Zhao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Circulating Tumor Dna ◽  
Chinese Patients ◽  
Advanced Hepatocellular Carcinoma ◽  
Genomic Profiling ◽  
Promising Alternative ◽  
Hybrid Capture ◽  
Advanced Hcc ◽  
Tissue Biopsy ◽  
Tumor Dna

e15606 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies with a particularly high prevalence in China. The genomic profiling in HCC had been widely explored with tissue biopsy, however, given the intrinsic risks of invasive approach, blood-based circulating tumor DNA (ctDNA) has been proposed as a promising alternative. In this study, we aim to investigate whether the ctDNA may serve as a reliable tool to provide a more accurate molecular snapshot of HCC in Chinese patients. Methods: Plasma samples from 385 Chinese patients with advanced HCC were assayed for somatic genomic alternations by hybrid capture-based next-generation sequencing (NGS) with 150 genes and a mean sequencing depth of more than 3000×. The results were compared with our internal tissue genomic database of Chinese HCC patients (N = 873) tested by NGS and TCGA database (N = 373) tested by whole exome sequencing. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: Among 385 patients with ctDNA testing, somatic genomic alternations were detected in 97% of the patients (median = 5 alterations/patient). The most prevalent SNV mutations from ctDNA sequencing were TP53 (45.7%), TERT (19.5%), CTNNB1 (12.5%), and LRP1B (8.3%) compared to our tissue database (TP53 (61.2%), CTNNB1 (15.6%), TERT (13.3%), and LRP1B (11.0%)). While in TCGA database, the most common SNV mutations were found in TP53 (30.1%), CTNNB1 (26.0%), LRP1B (8.8%), ARID1A (8.6%), and SPTA1 (7.5%). Moreover, the level of MSAF was associated with detectable variant types, evidenced by a significant higher MSAF level observed when amplifications (P < 0.0001) or fusions (P = 0.008) were detected in the samples. Conclusions: Molecular analysis of patients with advanced HCC through ctDNA can serve as a reliable alternative to tissue biopsy. Chinese HCC patients may have different mutational landscapes to Western population. The utility of ctDNA analysis can provide therapeutically exploitable genomic profiles to identify potentially actionable gene alterations for targeted therapies.

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