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1.
Cell ; 171(5): 1029-1041.e21, 2017 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-29056346

RESUMO

Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.


Assuntos
Neoplasias/genética , Neoplasias/patologia , Humanos , Mutação INDEL , Instabilidade de Microssatélites , Modelos Genéticos , Taxa de Mutação , Neoplasias/imunologia , Mutação Puntual , Polimorfismo de Nucleotídeo Único , Seleção Genética
3.
Nat Commun ; 12(1): 6910, 2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34824211

RESUMO

Most cancers are characterized by the somatic acquisition of genomic rearrangements during tumour evolution that eventually drive the oncogenesis. Here, using multiplatform sequencing technologies, we identify and characterize a remarkable mutational mechanism in human hepatocellular carcinoma caused by Hepatitis B virus, by which DNA molecules from the virus are inserted into the tumour genome causing dramatic changes in its configuration, including non-homologous chromosomal fusions, dicentric chromosomes and megabase-size telomeric deletions. This aberrant mutational mechanism, present in at least 8% of all HCC tumours, can provide the driver rearrangements that a cancer clone requires to survive and grow, including loss of relevant tumour suppressor genes. Most of these events are clonal and occur early during liver cancer evolution. Real-time timing estimation reveals some HBV-mediated rearrangements occur as early as two decades before cancer diagnosis. Overall, these data underscore the importance of characterising liver cancer genomes for patterns of HBV integration.


Assuntos
Carcinoma Hepatocelular/genética , DNA Viral , Genoma Humano , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/virologia , Regulação Neoplásica da Expressão Gênica , Humanos , Integração Viral , Sequenciamento Completo do Genoma
4.
Nat Commun ; 11(1): 5040, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028839

RESUMO

Bringing together cancer genomes from different projects increases power and allows the investigation of pan-cancer, molecular mechanisms. However, working with whole genomes sequenced over several years in different sequencing centres requires a framework to compare the quality of these sequences. We used the Pan-Cancer Analysis of Whole Genomes cohort as a test case to construct such a framework. This cohort contains whole cancer genomes of 2832 donors from 18 sequencing centres. We developed a non-redundant set of five quality control (QC) measurements to establish a star rating system. These QC measures reflect known differences in sequencing protocol and provide a guide to downstream analyses and allow for exclusion of samples of poor quality. We have found that this is an effective framework of quality measures. The implementation of the framework is available at: https://dockstore.org/containers/quay.io/jwerner_dkfz/pancanqc:1.2.2 .


Assuntos
Genoma Humano/genética , Genômica/normas , Neoplasias/genética , Controle de Qualidade , Mapeamento Cromossômico/normas , Cromossomos Humanos/genética , Análise Mutacional de DNA/normas , Feminino , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Masculino , Mutação , Software , Sequenciamento Completo do Genoma/normas
5.
Nat Genet ; 52(3): 306-319, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32024998

RESUMO

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.


Assuntos
Carcinogênese/genética , Rearranjo Gênico/genética , Genoma Humano/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Neoplasias/genética , Retroelementos/genética , Humanos , Neoplasias/patologia
7.
Curr Protoc Bioinformatics ; 56: 15.10.1-15.10.18, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27930805

RESUMO

CaVEMan is an expectation maximization-based somatic substitution-detection algorithm that is written in C. The algorithm analyzes sequence data from a test sample, such as a tumor relative to a reference normal sample from the same patient and the reference genome. It performs a comparative analysis of the tumor and normal sample to derive a probabilistic estimate for putative somatic substitutions. When combined with a set of validated post-hoc filters, CaVEMan generates a set of somatic substitution calls with high recall and positive predictive value. Here we provide instructions for using a wrapper script called cgpCaVEManWrapper, which runs the CaVEMan algorithm and additional downstream post-hoc filters. We describe both a simple one-shot run of cgpCaVEManWrapper and a more in-depth implementation suited to large-scale compute farms. © 2016 by John Wiley & Sons, Inc.


Assuntos
Biologia Computacional/métodos , Neoplasias/genética , Software , Algoritmos , Variação Genética/genética , Genoma , Humanos , Polimorfismo de Nucleotídeo Único/genética
8.
Curr Protoc Bioinformatics ; 56: 15.9.1-15.9.17, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27930809

RESUMO

We have developed ascatNgs to aid researchers in carrying out Allele-Specific Copy number Analysis of Tumours (ASCAT). ASCAT is capable of detecting DNA copy number changes affecting a tumor genome when comparing to a matched normal sample. Additionally, the algorithm estimates the amount of tumor DNA in the sample, known as Aberrant Cell Fraction (ACF). ASCAT itself is an R-package which requires the generation of many file types. Here, we present a suite of tools to help handle this for the user. Our code is available on our GitHub site (https://github.com/cancerit). This unit describes both 'one-shot' execution and approaches more suitable for large-scale compute farms. © 2016 by John Wiley & Sons, Inc.


Assuntos
Biologia Computacional/métodos , Variações do Número de Cópias de DNA/genética , Bases de Dados Genéticas , Algoritmos , Genoma , Humanos , Neoplasias/genética
9.
Nat Commun ; 7: 12605, 2016 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-27615322

RESUMO

Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.


Assuntos
Segunda Neoplasia Primária , Radiação Ionizante , Neoplasias da Mama , Dano ao DNA , Feminino , Deleção de Genes , Mutação em Linhagem Germinativa , Humanos , Masculino , Mutação , Osteossarcoma , Neoplasias da Próstata
10.
Curr Protoc Bioinformatics ; 52: 15.7.1-15.7.12, 2015 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-26678382

RESUMO

cgpPindel is a modified version of Pindel that is optimized for detecting somatic insertions and deletions (indels) in cancer genomes and other samples compared to a reference control. Post-hoc filters remove false positive calls, resulting in a high-quality dataset for downstream analysis. This unit provides concise instructions for both a simple 'one-shot' execution of cgpPindel and a more detailed approach suitable for large-scale compute farms.


Assuntos
Mutação INDEL/genética , Análise de Sequência de DNA/métodos , Software , Bases de Dados Genéticas , Humanos , Neoplasias/genética
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