Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 86
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nature ; 578(7793): 94-101, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025018

RESUMO

Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature1. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses3-15, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

2.
Nat Commun ; 11(1): 394, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959748

RESUMO

Ionising radiation (IR) is a recognised carcinogen responsible for cancer development in patients previously treated using radiotherapy, and in individuals exposed as a result of accidents at nuclear energy plants. However, the mutational signatures induced by distinct types and doses of radiation are unknown. Here, we analyse the genetic architecture of mammary tumours, lymphomas and sarcomas induced by high (56Fe-ions) or low (gamma) energy radiation in mice carrying Trp53 loss of function alleles. In mammary tumours, high-energy radiation is associated with induction of focal structural variants, leading to genomic instability and Met amplification. Gamma-radiation is linked to large-scale structural variants and a point mutation signature associated with oxidative stress. The genomic architecture of carcinomas, sarcomas and lymphomas arising in the same animals are significantly different. Our study illustrates the complex interactions between radiation quality, germline Trp53 deficiency and tissue/cell of origin in shaping the genomic landscape of IR-induced tumours.

3.
Nat Genet ; 52(1): 74-83, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31907488

RESUMO

The poor outcomes in esophageal adenocarcinoma (EAC) prompted us to interrogate the pattern and timing of metastatic spread. Whole-genome sequencing and phylogenetic analysis of 388 samples across 18 individuals with EAC showed, in 90% of patients, that multiple subclones from the primary tumor spread very rapidly from the primary site to form multiple metastases, including lymph nodes and distant tissues-a mode of dissemination that we term 'clonal diaspora'. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time points. These findings have implications for our understanding and clinical evaluation of EAC.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31932411

RESUMO

BACKGROUND: The link between modifiable breast cancer risk factors and tumor genomic alterations remains largely unexplored. We evaluated the association of prediagnostic body mass index (BMI), cigarette smoking, and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30), and nine driver mutations (CDH1, GATA3, KMT2C, MAP2K4, MAP3K1, NCOR1, PIK3CA, RUNX1, and TP53) in a subset of The Cancer Genome Atlas (TCGA). METHODS: Clinical and genomic data were retrieved from the TCGA database. Risk factor information was collected from four TCGA sites (n = 219 women), including BMI (1 year before diagnosis), cigarette smoking (smokers/nonsmokers), and alcohol consumption (current drinkers/nondrinkers). Multivariable regression analyses were conducted in all tumors and stratified according to estrogen receptor (ER) status. RESULTS: Increasing BMI was associated with increasing SCNV in all women (P = 0.039) and among women with ER- tumors (P = 0.031). Smokers had higher SCNV and TSMB versus nonsmokers (P < 0.05 all women). Alcohol drinkers had higher SCNV versus nondrinkers (P < 0.05 all women and among women with ER+ tumors). SBS3 (defective homologous recombination-based repair) was exclusively found in alcohol drinkers with ER- disease. GATA3 mutation was more likely to occur in women with higher BMI. No association was significant after multiple testing correction. CONCLUSIONS: This study provides preliminary evidence that BMI, cigarette smoking, and alcohol consumption can influence breast tumor biology, in particular, DNA alterations. IMPACT: This study demonstrates a link between modifiable breast cancer risk factors and tumor genomic alterations.

5.
Blood ; 135(1): 41-55, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31697823

RESUMO

To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.

6.
Nat Commun ; 10(1): 5546, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804466

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately mimic the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report a mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we find that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform to accelerate the development of immunotherapeutic options for HNSCC.

7.
Nucleic Acids Res ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31853541

RESUMO

UVA-induced mutagenesis was investigated in human pol eta-deficient (XP-V) cells through whole-exome sequencing. In UVA-irradiated cells, the increase in the mutation frequency in deficient cells included a remarkable contribution of C>T transitions, mainly at potential pyrimidine dimer sites. A strong contribution of C>A transversions, potentially due to oxidized bases, was also observed in non-irradiated XP-V cells, indicating that basal mutagenesis caused by oxidative stress may be related to internal tumours in XP-V patients. The low levels of mutations involving T induced by UVA indicate that pol eta is not responsible for correctly replicating T-containing pyrimidine dimers, a phenomenon known as the 'A-rule'. Moreover, the mutation signature profile of UVA-irradiated XP-V cells is highly similar to the human skin cancer profile, revealing how studies involving cells deficient in DNA damage processing may be useful to understand the mechanisms of environmentally induced carcinogenesis.

8.
Proc Natl Acad Sci U S A ; 116(45): 22730-22736, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31624127

RESUMO

The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring ERBB2 (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models (P = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.

9.
BMC Genomics ; 20(1): 685, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470794

RESUMO

BACKGROUND: Cancer genomes are peppered with somatic mutations imprinted by different mutational processes. The mutational pattern of a cancer genome can be used to identify and understand the etiology of the underlying mutational processes. A plethora of prior research has focused on examining mutational signatures and mutational patterns from single base substitutions and their immediate sequencing context. We recently demonstrated that further classification of small mutational events (including substitutions, insertions, deletions, and doublet substitutions) can be used to provide a deeper understanding of the mutational processes that have molded a cancer genome. However, there has been no standard tool that allows fast, accurate, and comprehensive classification for all types of small mutational events. RESULTS: Here, we present SigProfilerMatrixGenerator, a computational tool designed for optimized exploration and visualization of mutational patterns for all types of small mutational events. SigProfilerMatrixGenerator is written in Python with an R wrapper package provided for users that prefer working in an R environment. SigProfilerMatrixGenerator produces fourteen distinct matrices by considering transcriptional strand bias of individual events and by incorporating distinct classifications for single base substitutions, doublet base substitutions, and small insertions and deletions. While the tool provides a comprehensive classification of mutations, SigProfilerMatrixGenerator is also faster and more memory efficient than existing tools that generate only a single matrix. CONCLUSIONS: SigProfilerMatrixGenerator provides a standardized method for classifying small mutational events that is both efficient and scalable to large datasets. In addition to extending the classification of single base substitutions, the tool is the first to provide support for classifying doublet base substitutions and small insertions and deletions. SigProfilerMatrixGenerator is freely available at https://github.com/AlexandrovLab/SigProfilerMatrixGenerator with an extensive documentation at https://osf.io/s93d5/wiki/home/ .


Assuntos
Mutação , Neoplasias/genética , Software , Genômica/métodos , Humanos , Mutação INDEL
10.
JNCI Cancer Spectr ; 3(2): pkz028, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31360904

RESUMO

Background: It is often assumed any cancer in a germline BRCA1 or BRCA2 (collectively termed BRCA) mutation carrier was caused by that mutation. It is also often assumed the occurrence of breast or ovarian cancer in an individual with a variant of uncertain significance (VUS) suggests the VUS is pathogenic. These assumptions have profound management implications for cancer patients and healthy individuals. Methods: We compared the frequency of BRCA mutations, allele loss, and Signature 3 in 7632 individuals with 28 cancers and 1000 population controls. Because only increased frequency was the focus of the study, all statistical tests were one-sided. Results: Individuals with breast or ovarian cancer had increased germline BRCA pathogenic mutation frequencies compared to controls (P = 1.0x10-10 and P = 1.4x10-34, respectively). There was no increase in other cancer types. Wild-type allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers with BRCA mutations compared with other cancers with BRCA mutations (P = 5.1x10-10 and P = 3.7x10-9) and cancers without BRCA mutations (P = 2.8x10-53 and P = 1.0x10-134). There was no difference between non-breast and non-ovarian cancers with BRCA mutations and cancers without BRCA mutations. Allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers in individuals with BRCA pathogenic mutations compared to those with VUS (P = 3.8x10-17 and P = 1.6x10-8) or benign variants (P = 1.2x10-28 and P = 2.2x10-10). There was no difference between individuals with BRCA VUS and those with benign variants. Conclusions: These data show that non-breast and non-ovarian cancers in individuals with germline BRCA pathogenic mutations are often not causally related to the mutation and that BRCA VUS are highly unlikely to be pathogenic. These results should reduce inappropriate management of germline BRCA information.

11.
Nat Commun ; 10(1): 1749, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988298

RESUMO

Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA methylation variation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). Repression effects on tumor suppressor genes are negligible as they are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin and may represent tissue-specific silent regions which tolerate instability at the epigenetic, transcriptomic and genetic level.


Assuntos
Neoplasias da Mama/genética , Ilhas de CpG , Metilação de DNA , Epigênese Genética , Feminino , Humanos , Modelos Logísticos
12.
Cancer Cell ; 35(3): 441-456.e8, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30889380

RESUMO

Undifferentiated sarcomas (USARCs) of adults are diverse, rare, and aggressive soft tissue cancers. Recent sequencing efforts have confirmed that USARCs exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the molecular basis of the structural complexity in USARCs by integrating DNA sequencing, ploidy analysis, gene expression, and methylation profiling. We identified whole genome duplication as a prevalent and pernicious force in USARC tumorigenesis. Using mathematical deconvolution strategies to unravel the complex copy-number profiles and mutational timing models we infer distinct evolutionary pathways of these rare cancers. In addition, 15% of tumors exhibited raised mutational burdens that correlated with gene expression signatures of immune infiltration, and good prognosis.


Assuntos
Metilação de DNA , Perfilação da Expressão Gênica/métodos , Sarcoma/genética , Análise de Sequência de DNA/métodos , Evolução Molecular , Duplicação Gênica , Humanos , Mutação , Ploidias , Prognóstico
13.
Cell ; 176(6): 1282-1294.e20, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30849372

RESUMO

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.


Assuntos
Desaminases APOBEC/genética , Neoplasias/genética , Desaminases APOBEC/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , DNA/metabolismo , Análise Mutacional de DNA/métodos , Bases de Dados Genéticas , Exoma , Genoma Humano/genética , Xenoenxertos , Humanos , Mutagênese , Mutação/genética , Taxa de Mutação , Retroelementos , Sequenciamento Completo do Exoma/métodos
15.
Mol Cancer Res ; 17(4): 895-906, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30651371

RESUMO

To investigate the genomic evolution of metastatic pediatric osteosarcoma, we performed whole-genome and targeted deep sequencing on 14 osteosarcoma metastases and two primary tumors from four patients (two to eight samples per patient). All four patients harbored ancestral (truncal) somatic variants resulting in TP53 inactivation and cell-cycle aberrations, followed by divergence into relapse-specific lineages exhibiting a cisplatin-induced mutation signature. In three of the four patients, the cisplatin signature accounted for >40% of mutations detected in the metastatic samples. Mutations potentially acquired during cisplatin treatment included NF1 missense mutations of uncertain significance in two patients and a KIT G565R activating mutation in one patient. Three of four patients demonstrated widespread ploidy differences between samples from the sample patient. Single-cell seeding of metastasis was detected in most metastatic samples. Cross-seeding between metastatic sites was observed in one patient, whereas in another patient a minor clone from the primary tumor seeded both metastases analyzed. These results reveal extensive clonal heterogeneity in metastatic osteosarcoma, much of which is likely cisplatin-induced. IMPLICATIONS: The extent and consequences of chemotherapy-induced damage in pediatric cancers is unknown. We found that cisplatin treatment can potentially double the mutational burden in osteosarcoma, which has implications for optimizing therapy for recurrent, chemotherapy-resistant disease.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Cisplatino/uso terapêutico , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Antineoplásicos/farmacologia , Neoplasias Ósseas/patologia , Cisplatino/farmacologia , Evolução Clonal/efeitos dos fármacos , Análise Mutacional de DNA , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Modelos Genéticos , Mutagênese/efeitos dos fármacos , Metástase Neoplásica , Osteossarcoma/patologia , Sequenciamento Completo do Genoma
16.
Eur J Epidemiol ; 34(5): 439-445, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30623292

RESUMO

An intense scientific debate has recently taken place relating to the "bad luck" hypothesis in cancer development, namely that intrinsic random, and therefore unavoidable, mutagenic events would have a predominant role in tumorigenesis. In this article we review the main contributions to this debate and explain the reasons why the claim that cancer is mostly explained by intrinsic random factors is unsupported by data and theoretical models. In support of this, we present an analysis showing that smoking-induced mutations are more predictive of cancer risk than the lifetime number of stem cell cellular divisions.


Assuntos
Neoplasias/epidemiologia , Divisão Celular , Humanos , Mutação , Neoplasias/genética , Fatores de Risco , Células-Tronco/citologia
17.
J Hepatol ; 2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31899206

RESUMO

BACKGROUND&AIMS: Chronic alcohol (EtOH) consumption is a leading risk factor for development of hepatocellular carcinoma (HCC), which is associated with marked increase of hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. METHODS: Genetic deletion and pharmacological blocking was used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC. RESULTS: We demonstrate that global deletion of IL-17RA gene suppressed HCC in alcohol-fed DEN-challenged IL-17RA-/- and Mup-uPA/IL-17RA-/- mice compared to wild type mice. When the cell-specific role of IL-17RA signaling was examined, development of HCC was decreased in both alcohol-fed IL-17RAΔMΦ and IL-17RAΔHep mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in IL-17RAΔHSCs mice (deficient of IL-17RA in hepatic stellate cells (HSCs)). Deletion of IL-17RA in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed IL-17RAΔMΦ mice. Remarkably, despite a normal inflammatory response, alcohol-fed IL-17RAΔHep mice developed the fewest tumors (compared to IL-17RAΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated expression of Cxcl1 and other chemokines, exhibited a striking defect in TNF-TNFR1-dependent Caspase-2-SREBP-1/2-DHCR7-mediated cholesterol synthesis, and upregulated production of anti-oxidant Vitamin D3. Pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 Ab suppressed progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for treatment of alcohol-induced HCC. CONCLUSIONS: Overall, IL-17A is as a tumor promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC.

18.
PLoS One ; 13(12): e0206653, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532243

RESUMO

D-Wave quantum annealers represent a novel computational architecture and have attracted significant interest. Much of this interest has focused on the quantum behavior of D-Wave machines, and there have been few practical algorithms that use the D-Wave. Machine learning has been identified as an area where quantum annealing may be useful. Here, we show that the D-Wave 2X can be effectively used as part of an unsupervised machine learning method. This method takes a matrix as input and produces two low-rank matrices as output-one containing latent features in the data and another matrix describing how the features can be combined to approximately reproduce the input matrix. Despite the limited number of bits in the D-Wave hardware, this method is capable of handling a large input matrix. The D-Wave only limits the rank of the two output matrices. We apply this method to learn the features from a set of facial images and compare the performance of the D-Wave to two classical tools. This method is able to learn facial features and accurately reproduce the set of facial images. The performance of the D-Wave shows some promise, but has some limitations. It outperforms the two classical codes in a benchmark when only a short amount of computational time is allowed (200-20,000 microseconds), but these results suggest heuristics that would likely outperform the D-Wave in this benchmark.


Assuntos
Aprendizado de Máquina , Modelos Teóricos , Teoria Quântica
19.
Proc Natl Acad Sci U S A ; 115(42): E9879-E9888, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30287485

RESUMO

Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among the most complex cancers. This complexity is paralleled by dozens of mouse models that generate histologically similar tumors but have not been systematically validated at the molecular level. Accurate models of the molecular pathogenesis of HCC are essential for biomedical progress; therefore we compared genomic and transcriptomic profiles of four separate mouse models [MUP transgenic, TAK1-knockout, carcinogen-driven diethylnitrosamine (DEN), and Stelic Animal Model (STAM)] with those of 987 HCC patients with distinct etiologies. These four models differed substantially in their mutational load, mutational signatures, affected genes and pathways, and transcriptomes. STAM tumors were most molecularly similar to human HCC, with frequent mutations in Ctnnb1, similar pathway alterations, and high transcriptomic similarity to high-grade, proliferative human tumors with poor prognosis. In contrast, TAK1 tumors better reflected the mutational signature of human HCC and were transcriptionally similar to low-grade human tumors. DEN tumors were least similar to human disease and almost universally carried the Braf V637E mutation, which is rarely found in human HCC. Immune analysis revealed that strain-specific MHC-I genotype can influence the molecular makeup of murine tumors. Thus, different mouse models of HCC recapitulate distinct aspects of HCC biology, and their use should be adapted to specific questions based on the molecular features provided here.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Perfilação da Expressão Gênica , Genômica/métodos , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas/genética , Animais , Carcinoma Hepatocelular/patologia , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transcriptoma
20.
Nat Commun ; 9(1): 3667, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30202019

RESUMO

Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumour differentiation status suggest events which may drive disease progression. Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure to the immunosuppressive drug azathioprine. Characterisation of a panel of 15 cSCC tumour-derived cell lines reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a valuable resource for the validation of tumour drivers and therapeutic targets.


Assuntos
Azatioprina/uso terapêutico , Carcinoma de Células Escamosas/genética , Análise Mutacional de DNA , Mutação , Neoplasias Cutâneas/genética , Células 3T3 , Animais , Biópsia , Carcinoma de Células Escamosas/tratamento farmacológico , Diferenciação Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Exoma , Dosagem de Genes , Perfilação da Expressão Gênica , Genômica , Humanos , Imunossupressores/uso terapêutico , Estudos Longitudinais , Camundongos , Prognóstico , Análise de Sequência de DNA , Neoplasias Cutâneas/tratamento farmacológico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA