Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

Cell, Journal Year: 2017, Volume and Issue: 168(4), P. 613 - 628

Published: Feb. 1, 2017

Language: Английский

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Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures

Genome biology, Journal Year: 2016, Volume and Issue: 17(1)

Published: Nov. 17, 2016

Tumor-infiltrating immune cells have been linked to prognosis and response immunotherapy; however, the levels of distinct cell subsets signals that draw them into a tumor, such as expression antigen presenting machinery genes, remain poorly characterized. Here, we employ gene expression-based computational method profile infiltration 24 populations in 19 cancer types. We compare types using an score T find clear renal carcinoma (ccRCC) is among highest for both scores. Using profiles well transcriptomic proteomic datasets, characterize three groups ccRCC tumors: enriched, heterogeneously infiltrated, non-infiltrated. observe immunogenicity tumors cannot be explained by mutation load or neo-antigen load, but highly correlated with MHC class I (APM). explore prognostic value show two cohorts Th17 CD8+ T/Treg ratio are associated improved survival, whereas Th2 Tregs negative outcomes. Investigation association patterns subclonal architecture shows APM negatively subclone number. Our analysis sheds light on human cancers unravels mRNA signatures utility immunotherapeutic biomarker potential ccRCC.

Language: Английский

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Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance

Science Translational Medicine, Journal Year: 2017, Volume and Issue: 9(379)

Published: March 1, 2017

Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms resistance remain incompletely understood. To address this, we recently studied a cohort melanoma patients treated with sequential against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) identified immune markers resistance. Building on these studies, performed deep molecular profiling including cell receptor sequencing whole-exome within the same demonstrated that more clonal repertoire was predictive to PD-1 but not CTLA-4 blockade. Analysis CNAs higher burden copy number loss nonresponders found it associated decreased expression genes immune-related pathways. The effect mutational load nonredundant, suggesting potential utility combinatorial biomarker optimize patient care therapy.

Language: Английский

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Comprehensive Analysis of Hypermutation in Human Cancer

Cell, Journal Year: 2017, Volume and Issue: 171(5), P. 1042 - 1056.e10

Published: Oct. 19, 2017

Language: Английский

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The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

Nature Medicine, Journal Year: 2017, Volume and Issue: 24(1), P. 103 - 112

Published: Dec. 11, 2017

Language: Английский

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Resolving genetic heterogeneity in cancer

Nature Reviews Genetics, Journal Year: 2019, Volume and Issue: 20(7), P. 404 - 416

Published: March 27, 2019

Language: Английский

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PhyloWGS: Reconstructing subclonal composition and evolution from whole-genome sequencing of tumors

Genome Biology, Journal Year: 2015, Volume and Issue: 16(1)

Published: Feb. 12, 2015

Abstract Tumors often contain multiple subpopulations of cancerous cells defined by distinct somatic mutations. We describe a new method, PhyloWGS, which can be applied to whole-genome sequencing data from one or more tumor samples reconstruct complete genotypes these based on variant allele frequencies (VAFs) point mutations and population structural variations. introduce principled phylogenic correction for VAFs in loci affected copy number alterations we show that this greatly improves subclonal reconstruction compared existing methods. PhyloWGS is free, open-source software, available at https://github.com/morrislab/phylowgs .

Language: Английский

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Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution

Genome Research, Journal Year: 2015, Volume and Issue: 25(3), P. 316 - 327

Published: Feb. 3, 2015

Glioblastoma (GBM) is a prototypical heterogeneous brain tumor refractory to conventional therapy. A small residual population of cells escapes surgery and chemoradiation, resulting in typically fatal recurrence ∼7 mo after diagnosis. Understanding the molecular architecture this critical for development successful therapies. We used whole-genome sequencing whole-exome multiple sectors from primary paired recurrent GBM tumors reconstruct genomic profile residual, therapy resistant initiating cells. found that genetic alteration p53 pathway event predictive high number subclonal mutations glioblastoma. The road leading highly idiosyncratic but can be broadly classified into linear recurrences share extensive similarity with directly traced one its specific sectors, divergent few alterations originate branched off early during tumorigenesis. Our study provides mechanistic insights how impact ensuing evolution emergence heterogeneity.

Language: Английский

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Cancer Evolution: Mathematical Models and Computational Inference

Systematic Biology, Journal Year: 2014, Volume and Issue: 64(1), P. e1 - e25

Published: Oct. 7, 2014

Cancer is a somatic evolutionary process characterized by the accumulation of mutations, which contribute to tumor growth, clinical progression, immune escape, and drug resistance development. Evolutionary theory can be used analyze dynamics cell populations make inference about history from molecular data. We review recent approaches modeling evolution cancer, including population models initiation phylogenetic methods model relationship between subclones, probabilistic graphical describe dependencies among mutations. helps understand how tumors arise will also play an increasingly important prognostic role in predicting disease progression outcome medical interventions, such as targeted therapy.

Language: Английский

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Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia

Nature Medicine, Journal Year: 2016, Volume and Issue: 22(7), P. 792 - 799

Published: June 20, 2016

Language: Английский

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