Evolution of chromosome-arm aberrations in breast cancer through genetic network rewiring DOI Creative Commons
Elena Kuzmin, Toby M. Baker, Tom Lesluyes

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 113988 - 113988

Published: March 22, 2024

The basal breast cancer subtype is enriched for triple-negative (TNBC) and displays consistent large chromosomal deletions. Here, we characterize evolution maintenance of chromosome 4p (chr4p) loss in cancer. Analysis Cancer Genome Atlas data shows recurrent deletion chr4p Phylogenetic analysis a panel 23 primary tumor/patient-derived xenograft cancers reveals early deletion. Mechanistically show that associated with enhanced proliferation. Gene function studies identify an unknown gene, C4orf19, within chr4p, which suppresses proliferation when overexpressed—a member the PDCD10-GCKIII kinase module name PGCKA1. Genome-wide pooled overexpression screens using barcoded library human open reading frames regions, including suppress overexpressed context-dependent manner, implicating network interactions. Together, these results shed light on emergence complex aneuploid karyotypes involving adaptive landscapes shaping genomes.

Language: Английский

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes DOI Creative Commons
Stefan C. Dentro, Ignaty Leshchiner, Kerstin Haase

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(8), P. 2239 - 2254.e39

Published: April 1, 2021

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, drivers ITH across cancer types are poorly understood. To address this, we extensively characterize whole-genome sequences 2,658 samples spanning 38 types. Nearly all informative (95.1%) contain evidence distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection driver mutations most identify type-specific patterns gene mutations, fusions, structural variants, copy number alterations as well dynamic changes in mutational processes expansions. Our results underline importance its tumor evolution provide pan-cancer resource comprehensively annotated events from sequencing data.

Language: Английский

Citations

397
A clinically applicable integrative molecular classification of meningiomas DOI
Farshad Nassiri, Jeff Liu, Vikas Patil

et al.

Nature, Journal Year: 2021, Volume and Issue: 597(7874), P. 119 - 125

Published: Aug. 25, 2021

Language: Английский

Citations

297
Promises and challenges of adoptive T-cell therapies for solid tumours DOI Creative Commons
Matteo Morotti, Ashwag Albukhari, Abdulkhaliq Alsaadi

et al.

British Journal of Cancer, Journal Year: 2021, Volume and Issue: 124(11), P. 1759 - 1776

Published: March 29, 2021

Abstract Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous allogeneic transplant tumour-infiltrating lymphocytes genetically modified T cells expressing novel receptors chimeric antigen receptors, has shown promise in treatment cancer patients, durable responses some cases, cure. Technological advances genomics, computational biology, immunology cell manufacturing have brought aspiration individualised for closer reality. This era cell-based therapeutics challenges traditional standards therapeutic interventions provides opportunities paradigm shift our approach therapy. Invited speakers at 2020 symposium discussed three areas—cancer cell-therapy manufacturing—that are essential effective translation solid malignancies. Key been made understanding genetic intratumour heterogeneity, strategies accurately identify neoantigens, overcome exhaustion circumvent tumour immunosuppression after infusion being developed. Advances cell-manufacturing approaches that potential establish cell-therapies as credible options. face but hold great improving clinical outcomes tumours.

Language: Английский

Citations

203
Ordered and deterministic cancer genome evolution after p53 loss DOI Creative Commons
Timour Baslan, John P. Morris, Zhen Zhao

et al.

Nature, Journal Year: 2022, Volume and Issue: 608(7924), P. 795 - 802

Published: Aug. 17, 2022

Although p53 inactivation promotes genomic instability

Language: Английский

Citations

168
Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes DOI
Joshua J. Meeks, Hikmat Al‐Ahmadie, Bishoy M. Faltas

et al.

Nature Reviews Urology, Journal Year: 2020, Volume and Issue: 17(5), P. 259 - 270

Published: March 31, 2020

Language: Английский

Citations

162
Genomic and evolutionary classification of lung cancer in never smokers DOI
Tongwu Zhang, Philippe Joubert, Naser Ansari‐Pour

et al.

Nature Genetics, Journal Year: 2021, Volume and Issue: 53(9), P. 1348 - 1359

Published: Sept. 1, 2021

Language: Английский

Citations

156
A practical guide to cancer subclonal reconstruction from DNA sequencing DOI
Maxime Tarabichi, Adriana Salcedo, Amit G. Deshwar

et al.

Nature Methods, Journal Year: 2021, Volume and Issue: 18(2), P. 144 - 155

Published: Jan. 4, 2021

Language: Английский

Citations

153
Molecular phenotyping reveals the identity of Barrett’s esophagus and its malignant transition DOI
Karol Nowicki-Osuch, Lizhe Zhuang, Sriganesh Jammula

et al.

Science, Journal Year: 2021, Volume and Issue: 373(6556), P. 760 - 767

Published: Aug. 12, 2021

Identifying the origin of cancer Many cancers are classified on basis organ or tissue from which they originated. However, identifying specific cells and conditions that precede tumorigenesis can help us understand better treat resulting disease. Nowicki-Osuch et al . used a single-cell approach to investigate cell for Barrett’s esophagus (BE) mechanisms leading development esophageal adenocarcinoma (EAC) (see Perspective by Geboes Hoorens). Analyses healthy human tissues, mutational lineage tracing, organoid models revealed BE originates gastric cardia EAC arises undifferentiated cells. This analysis provides map transcriptional landscape be compared with mouse —LMZ

Language: Английский

Citations

134
Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma DOI Creative Commons
Oskar Marín-Béjar, Aljosja Rogiers, Michael Dewaele

et al.

Cancer Cell, Journal Year: 2021, Volume and Issue: 39(8), P. 1135 - 1149.e8

Published: June 17, 2021

Language: Английский

Citations

110
Detection of early seeding of Richter transformation in chronic lymphocytic leukemia DOI Creative Commons
Ferran Nadeu, Romina Royo, Ramon Massoni-Badosa

et al.

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(8), P. 1662 - 1671

Published: Aug. 1, 2022

Abstract Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into very aggressive large B cell lymphoma conferring dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses functional experiments, 19 cases CLL developing RT. Studying 54 longitudinal samples covering up to years disease course, we uncovered minute subclones carrying genomic, immunogenetic transcriptomic features cells already at diagnosis, which were dormant for before transformation. also identified new driver alterations, discovered mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS) high –B receptor (BCR) low -signaling transcriptional axis in showed that OXPHOS inhibition reduces proliferation cells. These findings demonstrate early seeding advanced stages cancer uncover potential therapeutic targets

Language: Английский

Citations

93