scholarly journals Individualized ctDNA Fingerprints to Monitor Treatment Response and Recurrence in Multiple Cancer Types

2019 ◽  
Author(s):  
Jiaping Li ◽  
Wei Jiang ◽  
Jinwang Wei ◽  
Jianwei Zhang ◽  
Linbo Cai ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Treatment Response ◽  
Whole Exome Sequencing ◽  
Therapeutic Response ◽  
Sequencing Data ◽  
Multiple Cancer ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Cancer Types

AbstractCirculating tumor DNA (ctDNA) panels hold high promise of accurately predicting the therapeutic response of tumors while being minimally invasive and cost-efficient. However, their use has been limited to a small number of tumor types and patients. Here, we developed individualized ctDNA fingerprints suitable for most patients with multiple cancer types. The panels were designed based on individual whole-exome sequencing data in 521 Chinese patients and targeting high clonal population clusters of somatic mutations. Together, these patients represent 12 types of cancers and seven different treatments. The customized ctDNA panels have a median somatic mutation number of 19, most of which are patient-specific rather than cancer hotspot mutations; 66.8% of the patients were ctDNA-positive. We further evaluated the ctDNA content fraction (CCF) of the mutations, and analyzed the association between the change of ctDNA concentration and therapeutic response. We followed up 106 patients for clinical evaluation, demonstrating a significant correlation of changes in ctDNA with clinical outcomes, with a consistency rate of 93.4%. In particular, the median CCF increased by 204.6% in patients with progressive disease, decreased by 82.5% in patients with remission, and was relatively stable in patients with stable disease. Overall, 85% of the patients with a ctDNA-positive status experienced metastasis or relapse long before imaging detection, except for two patients who developed recurrence and metastasis almost simultaneously. The average lead time between the first ctDNA-positive finding and radiological diagnosis was 76 days in three patients that changed from a ctDNA-negative to -positive status. Our individualized ctDNA analysis can effectively monitor the treatment response, metastasis, and recurrence in multiple cancer types in patients with multiple treatment options, therefore offering great clinical applicability for improving personalized treatment in cancer.One Sentence SummaryctDNA fingerprint panels were customized to predict the treatment response for multiple cancer types from individual whole-exome sequencing data.

scholarly journals EthSEQ: ethnicity annotation from whole exome sequencing data

2017 ◽  
Vol 33 (15) ◽  
pp. 2402-2404 ◽  
Author(s):  
Alessandro Romanel ◽  
Tuo Zhang ◽  
Olivier Elemento ◽  
Francesca Demichelis
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sequencing Data ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data

scholarly journals HPexome: An automated tool for processing whole-exome sequencing data

SoftwareX ◽  
2020 ◽  
Vol 11 ◽  
pp. 100478
Author(s):  
Lucas L. Cendes ◽  
Welliton de Souza ◽  
Iscia Lopes-Cendes ◽  
Benilton S. Carvalho
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sequencing Data ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Automated Tool

scholarly journals Assessing reliability of intra-tumor heterogeneity estimates from single sample whole exome sequencing data

PLoS ONE ◽  
2019 ◽  
Vol 14 (11) ◽  
pp. e0224143 ◽  
Author(s):  
Judith Abécassis ◽  
Anne-Sophie Hamy ◽  
Cécile Laurent ◽  
Benjamin Sadacca ◽  
Hélène Bonsang-Kitzis ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Tumor Heterogeneity ◽  
Single Sample ◽  
Sequencing Data ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data

Discovery of the First Pathogenic Human EPO Mutation Provides Mechanistic Insight into Cytokine Signaling

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 331-331
Author(s):  
Ah Ram Kim ◽  
Jacob C Ulirsch ◽  
Stephan Wilmes ◽  
Ekrem Unal ◽  
Ignacio Moraga ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Fluorescent Imaging ◽  
Binding Kinetics ◽  
Wild Type ◽  
Sequencing Data ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data

Abstract Congenital hypoplastic or Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder characterized by a paucity of red blood cells and their precursors in the bone marrow. The majority of cases of DBA are due to haploinsufficient mutations in ribosomal protein genes and in rare cases result from GATA1 mutations. However, nearly half of the DBA cases do not have an identified genetic etiology. While analyzing whole exome sequencing data from a cohort of over 450 patients with a clinical diagnosis of DBA, we encountered the case of a male child of a first cousin consanguineous union who was diagnosed with DBA as an infant and remained transfusion dependent. The patient responded to corticosteroid therapy for a year as a toddler, but this treatment was discontinued due to side effects. The patient subsequently remained transfusion dependent and at 6 years of age an allogeneic bone marrow transplant from a matched maternal aunt was performed. Surprisingly, despite achievement of robust donor chimerism, the patient remained transfusion dependent. Unfortunately the patient developed severe graft-versus-host disease and died of resultant complications. Both the potential recessive nature of the mutation, given parental consanguinity, and the lack of anemia correction following transplant made this case extremely unusual. Thus we evaluated this patient's whole exome sequencing data. We identified a homozygous recessive mutation in the erythropoietin gene (EPO), which resulted in an R150Q substitution in the mature EPO protein. This mutation was absent from a cohort of 60,706 individuals depleted for Mendelian disease and fit the model of complete penetrance in the family. The R150Q mutation was expected to disrupt the high-affinity binding site to the EPO receptor (EPOR). However, we found by producing recombinant proteins that the EPO R150Q mutation only reduced the EPOR binding affinity by 3-fold. Surprisingly, the patient had an over 100-fold elevation in their serum EPO levels, suggesting that this mutation did not cause disease through altered affinity. Rather we observed altered EPOR binding kinetics by this mutant ligand. There was a slightly increased on-rate with a much faster dissociation rate (t1/2 of 10 seconds for the mutant vs. 6 minutes for the wild type). Using human erythroid cells and primary hematopoietic stem and progenitor cells, we could show that this mutant ligand never reached the same efficacy as the wild type (WT) EPO in promoting erythroid differentiation and proliferation. To better characterize this abnormal activity, we examined downstream signaling responses. We found identical phosphorylation of STAT5 at maximally potent concentrations of the WT (1 nM) and R150Q mutant (100 nM) EPO. By surveying a broad array of >120 phosphorylation events using intracellular flow cytometry, we demonstrated that maximal levels of STAT3 and STAT1 phosphorylation were reduced by 30% and 25%, respectively, with the R150Q (100 nM) compared to WT (1 nM) EPO. To determine the mechanistic basis for variation in downstream effector activation by the R150Q mutant ligand, we used inhibitors of both the JAK2 kinase and the SHP1/2 phosphatases that are respectively up- and downstream of STAT phosphorylation. While SHP1/2 inhibition did not alter STAT phosphorylation, JAK2 inhibition by ruxolitinib more potently inhibited STAT1/3 phosphorylation compared to STAT5. Interestingly, treatment with a low dose of ruxolitinib (40 nM) reduced erythroid proliferation to the same extent at maximally potent concentrations of the WT or R150Q EPO, demonstrating that the impairment in signaling by the R150Q EPO was primarily due to reduced JAK2 activity. Finally, we utilized single molecule fluorescent imaging of EPOR dimerization at the intact cell surface to directly show that the kinetically-biased R150Q EPO has a reduced ability to promote productive dimerization as compared to the WT EPO, even at maximally potent concentrations. Collectively, our results demonstrate how the R150Q mutant EPO - the first pathogenic mutation in EPO identified in humans - results in biased agonism of EPOR signaling through reduced receptor dimerization and consequently impaired JAK2 activation. More broadly our findings reveal how variation of cytokine-receptor binding kinetics can be used to tune downstream responses, which has broad implications for modulating the activity of numerous hematopoietic cytokines. Disclosures No relevant conflicts of interest to declare.

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