Circulating tumor DNA (ctDNA) in patients with advanced adrenocortical carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4585-4585
Author(s):  
Bassel Nazha ◽  
Hiba I. Dada ◽  
Leylah Drusbosky ◽  
Jacqueline T Brown ◽  
Deepak Ravindranathan ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Treatment Options ◽  
Genomic Data ◽  
Circulating Tumor Dna ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Entire Cohort ◽  
Genomic Landscape ◽  
Ctdna Analysis

4585 Background: Adrenocortical Carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited treatments in the advanced setting. Molecular pathways with tumor suppressor genes (e.g. TP53, CDKN2A) and oncogenes (e.g. CTNNB1 and RAS) are implicated in oncogenesis. To our knowledge, the genomic landscape of ctDNA alterations for ACC has not been described in a large cohort. We report plasma-based ctDNA alterations in patients with advanced ACC. Methods: We retrospectively evaluated genomic data from 102 patients with ACC who had ctDNA testing between 12/2016 – 10/2020 using Guardant360 (Guardant Health, CA). ctDNA analysis interrogated single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes. We evaluated the frequency of genomic alterations, the landscape of co-occurring mutations, and pathogenic or likely pathogenic alterations with potential targeted therapies. The prevalence of alterations identified in ctDNA were compared to those detected in tissue using a publicly available database (cBioPortal). Results: The median age was 54 years (range 24-81), and 55% of patients were male. Among the entire cohort, 84 pts (82.4%) had ≥1 somatic alteration detected. Mutations were most frequently detected in TP53 (52%), EGFR (23%), CTNNB1 (18%), MET (18%), and ATM (14%). The frequencies detected in ctDNA were similar to the results detected in tissue. Pathogenic and/or likely pathogenic mutations in therapeutically relevant alterations were observed in 36 patients (35%), including EGFR, BRAF, MET, CDKN2A, and CDK4/6 (Table 1). The most frequently co-occurring mutations were EGFR + TP53 (14%), EGFR + MET (11%), BRAF + MET (10%). Conclusions: Blood-based ctDNA profiling in advanced ACC provided comprehensive genomic data in most patients, with a similar profile to tumor tissue analyses. Over one third of patients had actionable mutations with approved therapies in other cancers. This approach might inform the development of personalized treatment options for this aggressive malignancy.[Table: see text]

Landscape of circulating tumor DNA profiling of advanced pancreatic cancer (PDAC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 289-289
Author(s):  
Kabir Mody ◽  
Pashtoon Murtaza Kasi ◽  
Phani Keerthi Surapaneni ◽  
Mitesh J. Borad ◽  
Daniel H. Ahn ◽  
...  
Keyword(s):  
Treatment Options ◽  
Advanced Pancreatic Cancer ◽  
Gene Mutations ◽  
Median Number ◽  
Circulating Tumor Dna ◽  
Genomic Alteration ◽  
Single Nucleotide Variants ◽  
Tissue Biopsy ◽  
Ctdna Analysis ◽  
Tumor Dna

289 Background: PDAC has limited treatment options. Genomic analyses have led to development of targeted therapies now in several clinical trials, and may enable the discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Data regarding circulating tumor DNA (ctDNA) profiling in PDAC during real time clinical practice is limited. Methods: We performed ctDNA NGS analysis in pts with advanced PDAC (December 2014–August 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA), which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance (TR) was defined as possible treatments within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic Institutional Review Board requirements. Results: Among 171 pts and 206 total samples, ctDNA NGS revealed at least one genomic alteration in 150 pts (88%). Median number of alterations per patient was 3 [range, 1-15]. The total number of unique alterations was 450 with the most commonly altered genes being: TP53 (181 alterations, 40%), followed by KRAS (118 alterations, 26%), CDKN2A (23 alterations, 5%), SMAD4 (15 alterations, 3%), EGFR (11 alterations, 2.4%), PIK3CA (9 alterations, 2%), GNAS (8 alterations, 1.5%). Amplifications were noted in 16 genes, including BRAF, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, KIT, KRAS, MET, MYC, PDGFRA, PIK3CA and RAF1. Therapeutically relevant alterations were seen in 95 pts of the 150 pts (63%). Tissue based profiling (Results to be shown) was done in 56 (33%) pts of total 171 pts with a median of 130 days between ctDNA and tissue biopsy. KRAS and TP53 were the most common gene mutations found in patients with both liquid and tissue biopsy results. Conclusions: ctDNA plasma profiling of pts with advanced PDAC is a feasible alternative method to gather comprehensive genomic data.

Landscape of circulating tumor DNA and tissue-based profiling in advanced cholangiocarcinoma.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 291-291
Author(s):  
Kabir Mody ◽  
Pashtoon Murtaza Kasi ◽  
Phani Keerthi Surapaneni ◽  
Tanios S. Bekaii-Saab ◽  
Ramesh K. Ramanathan ◽  
...  
Keyword(s):  
Treatment Options ◽  
Gene Mutations ◽  
Median Number ◽  
Circulating Tumor Dna ◽  
Genomic Alteration ◽  
Single Nucleotide Variants ◽  
Synonymous Mutations ◽  
Tissue Biopsy ◽  
Ctdna Analysis ◽  
Tumor Dna

291 Background: Cholangiocarcinoma (CCA) has limited treatment options. Genomic analyses have led to development of targeted therapies now in clinical trials, and may enable discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Comparative data regarding circulating tumor DNA (ctDNA) analysis and tissue based profiling in CCA are limited. Methods: We performed ctDNA NGS analysis along with tissue based profiling in pts with advanced CCA (January 2015- February 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA) which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes and the majority of tissue based profiling using Foundation One. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance was defined as alterations within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic IRB requirements. Results: Among 124 pts and 139 total samples, ctDNA NGS revealed at least one genomic alteration (excluding variants of uncertain significance and synonymous mutations) in 89% of pts. Median number of alterations per pt was 3 [range, 1-15], with a median MAF of 0.42% (range, 0.1% - 94.2%). The total number of unique alterations was 321. The most commonly altered genes: TP53 (31%), KRAS (11%), FGFR2 (7%), APC and PIK3CA (each 5%) and ARID1A (3%). Amplifications were noted in 14 genes: BRAF, CCND1, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, MET, MYC, PDGFRA, and PIK3CA. Tissue-based profiling was available in 57 (46%) pts, with a median of 63 days between liquid and tissue biopsy. IDH1, FGFR2, TP53 and KRAS were most common gene mutations found in pts who had both liquid and tissue biopsy done. (Comparative results to be shown). Conclusions: ctDNA plasma profiling of pts with advanced CCA is a feasible alternative method to gather comprehensive genomic data. Further larger cohort studies comparing landscape of alterations seen on ctDNA versus tissue-based assays are needed.

scholarly journals Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans

2021 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Nayoung Han ◽  
Jung Mi Oh ◽  
In-Wha Kim
Keyword(s):  
Copy Number ◽  
Genome Wide Association Study ◽  
Copy Number Gain ◽  
Copy Number Variations ◽  
Gene Gain ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Haplotype Blocks ◽  
Genome Wide ◽  
Control And Prevention

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.

scholarly journals Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gillian Vandekerkhove ◽  
Jean-Michel Lavoie ◽  
Matti Annala ◽  
Andrew J. Murtha ◽  
Nora Sundahl ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Treatment Options ◽  
Circulating Tumor Dna ◽  
Molecular Stratification ◽  
Clinical Biomarkers ◽  
Surgery Patient ◽  
Metastatic Urothelial Carcinoma ◽  
Ctdna Analysis ◽  
Clinical Genomic ◽  
Tumor Dna

AbstractMolecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.

scholarly journals Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

2021 ◽  
Author(s):  
Pauline Arnaud ◽  
Hélène Morel ◽  
Olivier Milleron ◽  
Laurent Gouya ◽  
Christine Francannet ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Somatic Mosaicism ◽  
Variant Calling ◽  
Copy Number Variations ◽  
Pathogenic Variant ◽  
Single Nucleotide Variants ◽  
Bioinformatics Analyses ◽  
Single Nucleotide ◽  
Fbn1 Gene ◽  
Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

scholarly journals Multi-omics analysis to identify driving factors in colorectal cancer

Epigenomics ◽  
2020 ◽  
Vol 12 (18) ◽  
pp. 1633-1650
Author(s):  
Xi Xu ◽  
Chaoju Gong ◽  
Yunfeng Wang ◽  
Yanyan Hu ◽  
Hong Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Copy Number Variations ◽  
The Cancer Genome Atlas ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Omics Analysis ◽  
Competing Endogenous Rna Network ◽  
Cancer Genome Atlas

Aim: We aim to identify driving genes of colorectal cancer (CRC) through multi-omics analysis. Materials & methods: We downloaded multi-omics data of CRC from The Cancer Genome Atlas dataset. Integrative analysis of single-nucleotide variants, copy number variations, DNA methylation and differentially expressed genes identified candidate genes that carry CRC risk. Kernal genes were extracted from the weighted gene co-expression network analysis. A competing endogenous RNA network composed of CRC-related genes was constructed. Biological roles of genes were further investigated in vitro. Results: We identified LRRC26 and REP15 as novel prognosis-related driving genes for CRC. LRRC26 hindered tumorigenesis of CRC in vitro. Conclusion: Our study identified novel driving genes and may provide new insights into the molecular mechanisms of CRC.

scholarly journals Comprehensive Custom NGS Panel Validation for the Improvement of the Stratification of B-Acute Lymphoblastic Leukemia Patients

2020 ◽  
Vol 10 (3) ◽  
pp. 137
Author(s):  
Adrián Montaño ◽  
Jesús Hernández-Sánchez ◽  
Maribel Forero-Castro ◽  
María Matorra-Miguel ◽  
Eva Lumbreras ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Wide Spectrum ◽  
Lymphoblastic Leukemia ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Single Step ◽  
Fusion Genes ◽  
Single Nucleotide Variants ◽  
Single Nucleotide

Background: B-acute lymphoblastic leukemia (B-ALL) is a hematological neoplasm of the stem lymphoid cell of the B lineage, characterized by the presence of genetic alterations closely related to the course of the disease. The number of alterations identified in these patients grows as studies of the disease progress, but in clinical practice, the conventional techniques frequently used are only capable of detecting the most common alterations. However, techniques, such as next-generation sequencing (NGS), are being implemented to detect a wide spectrum of new alterations that also include point mutations. Methods: In this study, we designed and validated a comprehensive custom NGS panel to detect the main genetic alterations present in the disease in a single step. For this purpose, 75 B-ALL diagnosis samples from patients previously characterized by standard-of-care diagnostic techniques were sequenced. Results: The use of the custom NGS panel allowed the correct detection of the main genetic alterations present in B-ALL patients, including the presence of an aneuploid clone in 14 of the samples and some of the recurrent fusion genes in 35 of the samples. The panel was also able to successfully detect a number of secondary alterations, such as single nucleotide variants (SNVs) and copy number variations (CNVs) in 66 and 46 of the samples analyzed, respectively, allowing for further refinement of the stratification of patients. The custom NGS panel could also detect alterations with a high level of sensitivity and reproducibility when the findings obtained by NGS were compared with those obtained from other conventional techniques. Conclusions: The use of this custom NGS panel allows us to quickly and efficiently detect the main genetic alterations present in B-ALL patients in a single assay (SNVs and insertions/deletions (INDELs), recurrent fusion genes, CNVs, aneuploidies, and single nucleotide polymorphisms (SNPs) associated with pharmacogenetics). The application of this panel would thus allow us to speed up and simplify the molecular diagnosis of patients, helping patient stratification and management.

Sign in / Sign up

Export Citation Format

Share Document