Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing

Nature Communications, Journal Year: 2017, Volume and Issue: 8(1)

Published: Aug. 8, 2017

Abstract In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of “fitter” clones may be anticipated. However, an imbalanced distribution frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into spatial clonal architecture. We demonstrate genomic heterogeneity more than 75% patients, inactivation CDKN2C TP53 , mutations affecting mitogen-activated protein kinase genes. show that extent positively associated with size biopsied lesions consistent regional outgrowth advanced clones. The results support model for progression sweeps early phase evolution disease. suggest investigations are critical understanding intra-patient evolutionary processes myeloma.

Language: Английский

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UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma

Cell, Journal Year: 2019, Volume and Issue: 179(1), P. 219 - 235.e21

Published: Sept. 1, 2019

Language: Английский

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Identification of neoantigens for individualized therapeutic cancer vaccines

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(4), P. 261 - 282

Published: Feb. 1, 2022

Language: Английский

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Machine learning approaches to drug response prediction: challenges and recent progress

npj Precision Oncology, Journal Year: 2020, Volume and Issue: 4(1)

Published: June 15, 2020

Abstract Cancer is a leading cause of death worldwide. Identifying the best treatment using computational models to personalize drug response prediction holds great promise improve patient’s chances successful recovery. Unfortunately, task predicting very challenging, partially due limitations available data and algorithmic shortcomings. The recent advances in deep learning may open new chapter search for ultimately result more accurate tools therapy response. This review provides an overview challenges prediction, focuses on comparing machine techniques be utmost practical use clinicians non-experts. incorporation modalities such as single-cell profiling, along with that rapidly find effective combinations will likely instrumental improving cancer care.

Language: Английский

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Tumor evolution: Linear, branching, neutral or punctuated?

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2017, Volume and Issue: 1867(2), P. 151 - 161

Published: Jan. 19, 2017

Language: Английский

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Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors

Nature Communications, Journal Year: 2017, Volume and Issue: 8(1)

Published: Feb. 10, 2017

Abstract Colorectal carcinoma represents a heterogeneous entity, with only fraction of the tumours responding to available therapies, requiring better molecular understanding disease in precision oncology. To address this challenge, OncoTrack consortium recruited 106 CRC patients (stages I–IV) and developed pre-clinical platform generating compendium drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived vivo vitro models. This large biobank tumours, 35 organoids 59 xenografts, extensive omics comparing donor derived models provides resource for advancing our CRC. Models recapitulate many genetic transcriptomic features donors, but defined less complex sub-groups because loss human stroma. Linking profiles patterns identifies novel biomarkers, including signature outperforming RAS/RAF mutations predicting EGFR inhibitor cetuximab.

Language: Английский

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The evolution of tumour phylogenetics: principles and practice

Nature Reviews Genetics, Journal Year: 2017, Volume and Issue: 18(4), P. 213 - 229

Published: Feb. 13, 2017

Language: Английский

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Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study

The Lancet Oncology, Journal Year: 2016, Volume and Issue: 18(1), P. 112 - 121

Published: Dec. 4, 2016

Language: Английский

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Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy

Cancer Discovery, Journal Year: 2016, Volume and Issue: 6(11), P. 1230 - 1236

Published: Sept. 29, 2016

We present the case of a patient with left frontal glioblastoma primitive neuroectodermal tumor features and hypermutated genotype in setting POLE germline alteration. During standard-of-care chemoradiation, developed cervical spine metastasis was subsequently treated pembrolizumab. Shortly thereafter, an additional metastatic spinal lesion. Using whole-exome DNA sequencing clonal analysis, we report changes subclonal architecture throughout treatment. Furthermore, persistently high neoantigen load observed within all tumors. Interestingly, following initiation pembrolizumab, brisk lymphocyte infiltration resected lesion objective radiographic response noted progressive intracranial lesion, suggestive active central nervous system (CNS) immunosurveillance checkpoint blockade therapy.It is unclear whether glioblastomas are susceptible to adults. Herein, provide proof principle that DNA-repair defects may result CNS immune activation, leading clinically immunologically significant responses. These patients represent genomically stratified group for whom immunotherapy could be considered. Cancer Discov; 6(11); 1230-6. ©2016 AACR.See related commentary by Snyder Wolchok, p. 1210This article highlighted In This Issue feature, 1197.

Language: Английский

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The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: Sept. 4, 2018

Abstract Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and moderately/poorly differentiated with accompanying clinical data longitudinal study of immunosuppressed immunocompetent patients integrate this analysis independent gene expression studies. We identify commonly mutated genes, copy number changes altered pathways processes. Comparisons differentiation status suggest events which may drive disease progression. Mutational signature reveals the presence novel (signature 32), whose incidence correlates chronic exposure to immunosuppressive drug azathioprine. Characterisation panel 15 tumour-derived lines that they accurately reflect signatures genomic alterations tumours provide valuable resource for validation drivers therapeutic targets.

Language: Английский

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