Pan-cancer whole-genome analyses of metastatic solid tumours

Nature, Journal Year: 2019, Volume and Issue: 575(7781), P. 210 - 216

Published: Oct. 23, 2019

Abstract Metastatic cancer is a major cause of death and associated with poor treatment efficacy. A better understanding the characteristics late-stage required to help adapt personalized treatments, reduce overtreatment improve outcomes. Here we describe largest, our knowledge, pan-cancer study metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs normal tissue, analysed at median depths 106× 38×, respectively, surveying more than 70 million somatic variants. The characteristic mutations lesions varied widely, that reflect those primary types, high rates duplication events (56%). Individual were relatively homogeneous, vast majority (96%) driver being clonal up 80% tumour-suppressor genes inactivated bi-allelically by different mutational mechanisms. Although genomes showed similar landscape tumours, find could contribute responsiveness therapy or resistance in individual patients. We implement an approach review clinically relevant associations their potential actionability. For 62% patients, identify genetic variants may be used stratify patients towards therapies either have been approved are clinical trials. This demonstrates importance comprehensive genomic profiling precision medicine cancer.

Language: Английский

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The landscape of somatic mutation in normal colorectal epithelial cells

Nature, Journal Year: 2019, Volume and Issue: 574(7779), P. 532 - 537

Published: Oct. 23, 2019

Language: Английский

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A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies

Nature Cancer, Journal Year: 2020, Volume and Issue: 1(2), P. 249 - 263

Published: Feb. 17, 2020

Language: Английский

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The metabolic landscape of RAS-driven cancers from biology to therapy

Nature Cancer, Journal Year: 2021, Volume and Issue: 2(3), P. 271 - 283

Published: March 24, 2021

Language: Английский

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A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Feb. 5, 2020

Abstract In cancer, the primary tumour’s organ of origin and histopathology are strongest determinants its clinical behaviour, but in 3% cases a patient presents with metastatic tumour no obvious primary. Here, as part ICGC/TCGA Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium , we train deep learning classifier to predict cancer type based on patterns somatic passenger mutations detected whole genome sequencing (WGS) 2606 tumours representing 24 common types produced by PCAWG Consortium. Our achieves an accuracy 91% held-out tumor samples 88% 83% respectively independent samples, roughly double trained pathologists when presented without knowledge Surprisingly, adding information driver reduced accuracy. results have applicability, underscore how encode state cell origin, can inform future strategies detect source circulating DNA.

Language: Английский

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The road ahead in genetics and genomics

Nature Reviews Genetics, Journal Year: 2020, Volume and Issue: 21(10), P. 581 - 596

Published: Aug. 24, 2020

Language: Английский

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Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Oct. 16, 2020

Abstract To increase understanding of the genomic landscape acral melanoma, a rare form melanoma occurring on palms, soles or nail beds, whole genome sequencing 87 tumors with matching transcriptome for 63 was performed. Here we report that mutational signature analysis reveals subset tumors, mostly subungual, an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS , NF1 NOTCH2 PTEN and TYRP1 . Mutations amplification KIT also common. Structural rearrangement copy number signatures show duplication, aneuploidy complex rearrangements Complex occur recurrently associated TERT CDK4 MDM2 CCND1 PAK1 GAB2 indicating potential therapeutic options.

Language: Английский

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Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis

Genome biology, Journal Year: 2018, Volume and Issue: 19(1)

Published: Dec. 1, 2018

DNA is subject to constant chemical modification and damage, which eventually results in variable mutation rates throughout the genome. Although detailed molecular mechanisms of damage repair are well understood, impact execution across a genome remain poorly defined.To bridge gap between our understanding distributions, we developed novel method, AP-seq, capable mapping apurinic sites 8-oxo-7,8-dihydroguanine bases at approximately 250-bp resolution on genome-wide scale. We directly demonstrate that accumulation rate varies widely genome, with hot spots acquiring many times more than cold spots. Unlike single nucleotide variants (SNVs) cancers, burden correlates marks for open chromatin notably H3K9ac H3K4me2. Apurinic oxidative also highly enriched transposable elements other repetitive sequences. In contrast, observe reduction loop anchors increased load towards inactive compartments. Less found promoters, exons, termination sites, but not introns, seemingly transcription-independent GC content-dependent manner. Leveraging cancer genomic data, find locally reduced SNV coding sequence, functional elements.Our study reveals differ strongly culminate previously unappreciated mechanism safeguards regulatory regions genes from mutations.

Language: Английский

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In silico saturation mutagenesis of cancer genes

Nature, Journal Year: 2021, Volume and Issue: 596(7872), P. 428 - 432

Published: July 28, 2021

Language: Английский

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Spatial structure governs the mode of tumour evolution

Nature Ecology & Evolution, Journal Year: 2021, Volume and Issue: 6(2), P. 207 - 217

Published: Dec. 23, 2021

Characterizing the mode-the way, manner or pattern-of evolution in tumours is important for clinical forecasting and optimizing cancer treatment. Sequencing studies have inferred various modes, including branching, punctuated neutral evolution, but it unclear why a particular pattern predominates any given tumour. Here we propose that tumour architecture key to explaining variety of observed genetic patterns. We examine this hypothesis using spatially explicit population genetics models demonstrate that, within biologically relevant parameter ranges, different spatial structures can generate four evolutionary modes: rapid clonal expansion, progressive diversification, branching effectively almost evolution. Quantitative indices describing classifying these modes are presented. Using indices, show our model predictions consistent with empirical observations types corresponding structures. The cell dispersal range cell-cell interactions found be essential factors accurately characterizing, controlling

Language: Английский

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