Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours

Nature, Journal Year: 2018, Volume and Issue: 555(7696), P. 371 - 376

Published: Feb. 28, 2018

Abstract Analysis of molecular aberrations across multiple cancer types, known as pan-cancer analysis, identifies commonalities and differences in key biological processes that are dysregulated cells from diverse lineages. Pan-cancer analyses have been performed for adult 1,2,3,4 but not paediatric cancers, which commonly occur developing mesodermic rather than epithelial tissues 5 . Here we present a study somatic alterations, including single nucleotide variants, small insertions or deletions, structural variations, copy number gene fusions internal tandem duplications 1,699 leukaemias solid tumours six histotypes, with whole-genome, whole-exome transcriptome sequencing data processed under uniform analytical framework. We report 142 driver genes only 45% match those found studies; alterations variants constituted the majority (62%) events. Eleven genome-wide mutational signatures were identified, one attributed to ultraviolet-light exposure eight aneuploid leukaemias. Transcription mutant allele was detectable 34% protein-coding mutations, 20% exhibited allele-specific expression. These provide comprehensive genomic architecture cancers emphasize need cancer-specific development precision therapies.

Language: Английский

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Neoantigens: promising targets for cancer therapy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Jan. 6, 2023

Abstract Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by cells as a result various tumor-specific alterations, such genomic mutation, dysregulated RNA splicing, disordered post-translational modification, integrated viral open reading frames. recognized non-self trigger an immune response that is not subject to central peripheral tolerance. The quick identification prediction neoantigens been made possible advanced next-generation sequencing bioinformatic technologies. Compared tumor-associated antigens, highly immunogenic provide emerging targets personalized serve prospective predictors survival prognosis checkpoint blockade responses. therapies will be aided understanding mechanism underlying neoantigen-induced anti-tumor streamlining process neoantigen-based immunotherapies. This review provides overview on characterization outlines clinical applications immunotherapeutic strategies based neoantigens. We also explore their current status, inherent challenges, translation potential.

Language: Английский

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Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies

Cell stem cell, Journal Year: 2018, Volume and Issue: 22(2), P. 157 - 170

Published: Feb. 1, 2018

Language: Английский

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The genetic basis and cell of origin of mixed phenotype acute leukaemia

Nature, Journal Year: 2018, Volume and Issue: 562(7727), P. 373 - 379

Published: Sept. 11, 2018

Language: Английский

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RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia

Cell stem cell, Journal Year: 2020, Volume and Issue: 27(1), P. 64 - 80.e9

Published: May 12, 2020

Language: Английский

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Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers

New England Journal of Medicine, Journal Year: 2021, Volume and Issue: 384(10), P. 924 - 935

Published: March 10, 2021

Genomic analysis is essential for risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Whole-genome sequencing a potential replacement conventional cytogenetic and approaches, but its accuracy, feasibility, clinical utility have not been demonstrated.

Language: Английский

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A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(6), P. 1212 - 1223

Published: May 26, 2022

Language: Английский

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The genomic landscape of pediatric cancers: Implications for diagnosis and treatment

Science, Journal Year: 2019, Volume and Issue: 363(6432), P. 1170 - 1175

Published: March 14, 2019

The past decade has witnessed a major increase in our understanding of the genetic underpinnings childhood cancer. Genomic sequencing studies have highlighted key differences between pediatric and adult cancers. Whereas many cancers are characterized by high number somatic mutations, typically few mutations but higher prevalence germline alterations cancer predisposition genes. Also noteworthy is remarkable heterogeneity types that likely drive growth cancers, including copy alterations, gene fusions, enhancer hijacking events, chromoplexy. Because most genetically profiled only at diagnosis, mechanisms underlying tumor progression, therapy resistance, metastasis remain poorly understood. We discuss evidence points to need for more integrative approaches aimed identifying driver events both diagnosis relapse. also provide an overview aspects this age group.

Language: Английский

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Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia

Science Translational Medicine, Journal Year: 2020, Volume and Issue: 12(546)

Published: June 3, 2020

Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability predict groups of types cancer that will respond immune targeting remains limited. This study dissected complexity architecture AML at high resolution assessed its influence on therapeutic response. Using 442 primary bone marrow samples from three independent cohorts children adults we defined immune-infiltrated immune-depleted disease classes revealed critical differences gene expression across age molecular subtypes. Interferon (IFN)-γ-related mRNA profiles were predictive for both chemotherapy resistance response refractory/relapsed flotetuzumab immunotherapy. Our compendium microenvironmental protein provides insights into immuno-biology could inform delivery personalized immunotherapies IFN-γ-dominant

Language: Английский

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A Summary of the Inaugural WHO Classification of Pediatric Tumors: Transitioning from the Optical into the Molecular Era

Cancer Discovery, Journal Year: 2021, Volume and Issue: 12(2), P. 331 - 355

Published: Dec. 17, 2021

Abstract Pediatric tumors are uncommon, yet the leading cause of cancer-related death in childhood. Tumor types, molecular characteristics, and pathogenesis unique, often originating from a single genetic driver event. The specific diagnostic challenges childhood led to development first World Health Organization (WHO) Classification Tumors. classification is rooted multilayered approach, incorporating morphology, IHC, characteristics. volume organized according organ sites provides single, state-of-the-art compendium pediatric tumor types. A special emphasis was placed on “blastomas,” which variably recapitulate morphologic maturation organs they originate. Significance: In this review, we briefly summarize main features updates each chapter inaugural WHO Tumors, including its rapid transition mostly microscopic into molecularly driven systematically taking recent discoveries genomics account.

Language: Английский

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