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Cell ; 184(8): 2239-2254.e39, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33831375


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

Heterogeneidade Genética , Neoplasias/genética , Variações do Número de Cópias de DNA , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Bases de Dados Genéticas , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma
Nat Commun ; 11(1): 731, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024834


The type and genomic context of cancer mutations depend on their causes. These causes have been characterized using signatures that represent mutation types that co-occur in the same tumours. However, it remains unclear how mutation processes change during cancer evolution due to the lack of reliable methods to reconstruct evolutionary trajectories of mutational signature activity. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we present TrackSig, a new method that reconstructs these trajectories using optimal, joint segmentation and deconvolution of mutation type and allele frequencies from a single tumour sample. In simulations, we find TrackSig has a 3-5% activity reconstruction error, and 12% false detection rate. It outperforms an aggressive baseline in situations with branching evolution, CNA gain, and neutral mutations. Applied to data from 2658 tumours and 38 cancer types, TrackSig permits pan-cancer insight into evolutionary changes in mutational processes.

Biologia Computacional/métodos , Mutação , Neoplasias/genética , Simulação por Computador , Evolução Molecular , Frequência do Gene , Genoma Humano , Humanos , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma
Nature ; 578(7793): 122-128, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025013


Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.

Evolução Molecular , Genoma Humano/genética , Neoplasias/genética , Reparo do DNA/genética , Dosagem de Genes , Genes Supressores de Tumor , Variação Genética , Humanos , Mutagênese Insercional/genética
Pac Symp Biocomput ; 25: 238-249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31797600


Mutational signatures are patterns of mutation types, many of which are linked to known mutagenic processes. Signature activity represents the proportion of mutations a signature generates. In cancer, cells may gain advantageous phenotypes through mutation accumulation, causing rapid growth of that subpopulation within the tumour. The presence of many subclones can make cancers harder to treat and have other clinical implications. Reconstructing changes in signature activities can give insight into the evolution of cells within a tumour. Recently, we introduced a new method, TrackSig, to detect changes in signature activities across time from single bulk tumour sample. By design, TrackSig is unable to identify mutation populations with different frequencies but little to no difference in signature activity. Here we present an extension of this method, TrackSigFreq, which enables trajectory reconstruction based on both observed density of mutation frequencies and changes in mutational signature activities. TrackSigFreq preserves the advantages of TrackSig, namely optimal and rapid mutation clustering through segmentation, while extending it so that it can identify distinct mutation populations that share similar signature activities.

Genoma Humano , Neoplasias , Biologia Computacional , Frequência do Gene , Humanos , Mutação , Neoplasias/genética
Cell ; 173(4): 1003-1013.e15, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29681457


The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures. Specific genes are selectively mutated prior to or following subclonal diversification, including MTOR, NKX3-1, and RB1. Patients with low-risk monoclonal tumors rarely relapse after primary therapy (7%), while those with high-risk polyclonal tumors frequently do (61%). The presence of multiple subclones in an index biopsy may be necessary, but not sufficient, for relapse of localized prostate cancer, suggesting that evolution-aware biomarkers should be studied in prospective studies of low-risk tumors suitable for active surveillance.

Neoplasias da Próstata/patologia , Biomarcadores Tumorais/sangue , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Gradação de Tumores , Recidiva Local de Neoplasia , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Estudos Prospectivos , Neoplasias da Próstata/classificação , Neoplasias da Próstata/genética , Proteínas de Ligação a Retinoblastoma/genética , Proteínas de Ligação a Retinoblastoma/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo