scholarly journals Analysis of the Whole-Exome Sequencing of Tumor and Circulating Tumor DNA in Metastatic Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1905
Author(s):  
Russell J. Diefenbach ◽  
Jenny H. Lee ◽  
Dario Strbenac ◽  
Jean Y. H. Yang ◽  
Alexander M. Menzies ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Cancer Progression ◽  
Low Frequency ◽  
Circulating Tumor Dna ◽  
Response To Therapy ◽  
Driver Mutations ◽  
Whole Exome ◽  
Tumor Dna

The use of circulating tumor DNA (ctDNA) to monitor cancer progression and response to therapy has significant potential but there is only limited data on whether this technique can detect the presence of low frequency subclones that may ultimately confer therapy resistance. In this study, we sought to evaluate whether whole-exome sequencing (WES) of ctDNA could accurately profile the mutation landscape of metastatic melanoma. We used WES to identify variants in matched, tumor-derived genomic DNA (gDNA) and plasma-derived ctDNA isolated from a cohort of 10 metastatic cutaneous melanoma patients. WES parameters such as sequencing coverage and total sequencing reads were comparable between gDNA and ctDNA. The mutant allele frequency of common single nucleotide variants was lower in ctDNA, reflecting the lower read depth and minor fraction of ctDNA within the total circulating free DNA pool. There was also variable concordance between gDNA and ctDNA based on the total number and identity of detected variants and this was independent of the tumor biopsy site. Nevertheless, established melanoma driver mutations and several other melanoma-associated mutations were concordant between matched gDNA and ctDNA. This study highlights that WES of ctDNA could capture clinically relevant mutations present in melanoma metastases and that enhanced sequencing sensitivity will be required to identify low frequency mutations.

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.

scholarly journals Modeling clonal structure over narrow time frames via circulating tumor DNA in metastatic breast cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Zachary T. Weber ◽  
Katharine A. Collier ◽  
David Tallman ◽  
Juliet Forman ◽  
Sachet Shukla ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
High Frequency ◽  
Copy Number ◽  
Clinical Decision Making ◽  
Circulating Tumor Dna ◽  
Whole Exome ◽  
Time Frames ◽  
Tumor Dna

Abstract Background Circulating tumor DNA (ctDNA) offers minimally invasive means to repeatedly interrogate tumor genomes, providing opportunities to monitor clonal dynamics induced by metastasis and therapeutic selective pressures. In metastatic cancers, ctDNA profiling allows for simultaneous analysis of both local and distant sites of recurrence. Despite the promise of ctDNA sampling, its utility in real-time genetic monitoring remains largely unexplored. Methods In this exploratory analysis, we characterize high-frequency ctDNA sample series collected over narrow time frames from seven patients with metastatic triple-negative breast cancer, each undergoing treatment with Cabozantinib, a multi-tyrosine kinase inhibitor (NCT01738438, https://clinicaltrials.gov/ct2/show/NCT01738438). Applying orthogonal whole exome sequencing, ultra-low pass whole genome sequencing, and 396-gene targeted panel sequencing, we analyzed 42 plasma-derived ctDNA libraries, representing 4–8 samples per patient with 6–42 days between samples. Integrating tumor fraction, copy number, and somatic variant information, we model tumor clonal dynamics, predict neoantigens, and evaluate consistency of genomic information from orthogonal assays. Results We measured considerable variation in ctDNA tumor faction in each patient, often conflicting with RECIST imaging response metrics. In orthogonal sequencing, we found high concordance between targeted panel and whole exome sequencing in both variant detection and variant allele frequency estimation (specificity = 95.5%, VAF correlation, r = 0.949), Copy number remained generally stable, despite resolution limitations posed by low tumor fraction. Through modeling, we inferred and tracked distinct clonal populations specific to each patient and built phylogenetic trees revealing alterations in hallmark breast cancer drivers, including TP53, PIK3CA, CDK4, and PTEN. Our modeling revealed varied responses to therapy, with some individuals displaying stable clonal profiles, while others showed signs of substantial expansion or reduction in prevalence, with characteristic alterations of varied literature annotation in relation to the study drug. Finally, we predicted and tracked neoantigen-producing alterations across time, exposing translationally relevant detection patterns. Conclusions Despite technical challenges arising from low tumor content, metastatic ctDNA monitoring can aid our understanding of response and progression, while minimizing patient risk and discomfort. In this study, we demonstrate the potential for high-frequency monitoring of evolving genomic features, providing an important step toward scalable, translational genomics for clinical decision making.

scholarly journals MBRS-26. WHOLE EXOME SEQUENCING OF CIRCULATING TUMOR DNA EXTRACTED FROM THE CEREBROSPINAL FLUID ALLOWS A PANGENOMIC CHARACTERISTISATION OF THE PRIMARY TUMOR

2018 ◽  
Vol 20 (suppl_2) ◽  
pp. i133-i134
Author(s):  
Mathieu Chicard ◽  
Valérie Combaret ◽  
Adrien Danzon ◽  
Nathalie Clément ◽  
Julien Masliah-Planchon ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Primary Tumor ◽  
Circulating Tumor Dna ◽  
Whole Exome ◽  
Tumor Dna

Whole exome sequencing (WES) of circulating tumor DNA (ctDNA) in patients with neuroendocrine prostate cancer (NEPC) informs tumor heterogeneity.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5011-5011 ◽  
Author(s):  
Himisha Beltran ◽  
Alessandro Romanel ◽  
Nicola Casiraghi ◽  
Michael Sigouros ◽  
Matteo Benelli ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Ad Hoc ◽  
Clonal Evolution ◽  
Circulating Tumor Dna ◽  
Tumor Biopsy ◽  
Invasive Approach ◽  
Genomic Changes ◽  
Whole Exome ◽  
Tumor Dna

5011 Background: We recently identified mechanisms underlying the clonal evolution of castration-resistant prostate adenocarcinoma (CRPC-Adeno) to a neuroendocrine resistance phenotype (Beltran et al, Nat Med 2016). We aimed to develop a non-invasive approach to identify patients that are developing NEPC. Methods: We performed whole exome sequencing of matched ctDNA, germline DNA, and metastatic biopsies from patients with CRPC-Adeno and NEPC. After applying ad hoc partial duplication filtering, we used FACETS and extended CLONET to calculate the fraction of tumor DNA and clonality of genomic lesions. Results: 64 CRPC patients were prospectively enrolled. The spectrum of alterations captured by WES of ctDNA was consistent with those commonly observed in CRPC validating the feasibility of the approach. The similarity of copy number alterations between tumor tissue and ctDNA was higher in NEPC compared to CRPC-Adeno (p = 0.0001) suggesting less heterogeneity in NEPC. There was enrichment of RB1 and TP53 loss in NEPC ctDNA and ARgains in CRPC-Adeno. The overall fraction of mutations shared by ctDNA and tumoral tissue was ~80%. We compared three different tumor biopsy time-points of patient PM161—CRPC-Adeno (lymph node), CRPC-Adeno (bone), NEPC (liver). Unexpectedly the baseline ctDNA profile (at time of CRPC-Adeno) displayed genomic features most similar to the NEPC liver biopsy. These data suggest that NEPC alterations are detectable in the circulation potentially prior to the development of NEPC clinical features. We compared the ctDNA of another patient PM0 with 6 sites of NEPC metastases obtained 6 days later at autopsy; the relative contribution of tumor alterations in ctDNA was highest for the liver metastasis (similarity 0.59) versus other sites suggesting differential contribution of metastatic sites in the circulation, with implications for the interpretation of single site clinical biopsies. Conclusions: This is the first study to show that WES of ctDNA is feasible in CRPC and can help elucidate intra-patient heterogeneity and identify the spectrum and frequency of NEPC genomic changes. ctDNA may improve the detection of patients transforming towards NEPC.

Whole-exome sequencing of chondroid hamartoma of lung identified no driver mutations

2018 ◽  
Vol 214 (3) ◽  
pp. 459-462
Author(s):  
Su Hye Choi ◽  
Hyeon-Chun Park ◽  
Min Sung Kim ◽  
Yeun-Jun Chung ◽  
Sug Hyung Lee
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Driver Mutations ◽  
Whole Exome
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