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1.
Cell Rep ; 34(4): 108670, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33503434

RESUMO

Inflammation-dependent base deaminases promote therapeutic resistance in many malignancies. However, their roles in human pre-leukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) had not been elucidated. Comparative whole-genome and whole-transcriptome sequencing analyses of FACS-purified pre-LSCs from myeloproliferative neoplasm (MPN) patients reveal APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell (HSPC) proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression. In pre-LSCs, inflammatory splice isoform overexpression coincides with APOBEC3C upregulation and ADAR1p150-induced A-to-I RNA hyper-editing. Pre-LSC evolution to LSCs is marked by STAT3 editing, STAT3ß isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown. Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching. Thus, pre-LSC evolution to LSCs is fueled by primate-specific APOBEC3C-induced pre-LSC proliferation and ADAR1-mediated splicing deregulation.

2.
Methods Mol Biol ; 2185: 447-473, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33165866

RESUMO

The genome of a cancer contains somatic mutations that reflect the activities of endogenous and exogenous mutational processes, with each mutational process imprinting a characteristic mutational signature. Computational analysis of somatic mutations derived from next-generation sequencing data allows revealing the mutational signatures operative in a set of cancer genomes. In this chapter, we briefly review the concept of mutational signatures and the tools available for deciphering mutational signatures. Further, we provide a quick guide as well as an in-depth protocol for deciphering mutational signatures using the tool SigProfilerExtractor and review the results generated from an example dataset of cancer genomes.

3.
BMC Bioinformatics ; 21(1): 438, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028213

RESUMO

BACKGROUND: Performing a statistical test requires a null hypothesis. In cancer genomics, a key challenge is the fast generation of accurate somatic mutational landscapes that can be used as a realistic null hypothesis for making biological discoveries. RESULTS: Here we present SigProfilerSimulator, a powerful tool that is capable of simulating the mutational landscapes of thousands of cancer genomes at different resolutions within seconds. Applying SigProfilerSimulator to 2144 whole-genome sequenced cancers reveals: (i) that most doublet base substitutions are not due to two adjacent single base substitutions but likely occur as single genomic events; (ii) that an extended sequencing context of ± 2 bp is required to more completely capture the patterns of substitution mutational signatures in human cancer; (iii) information on false-positive discovery rate of commonly used bioinformatics tools for detecting driver genes. CONCLUSIONS: SigProfilerSimulator's breadth of features allows one to construct a tailored null hypothesis and use it for evaluating the accuracy of other bioinformatics tools or for downstream statistical analysis for biological discoveries. SigProfilerSimulator is freely available at https://github.com/AlexandrovLab/SigProfilerSimulator with an extensive documentation at https://osf.io/usxjz/wiki/home/ .


Assuntos
Neoplasias/patologia , Interface Usuário-Computador , Mapeamento Cromossômico , Genômica/métodos , Humanos , Melanoma/genética , Melanoma/patologia , Mutação , Neoplasias/genética , Sequenciamento Completo do Genoma
4.
Nat Genet ; 52(11): 1189-1197, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32989322

RESUMO

Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analyzing tumor genomes from mice chronically exposed to 1 of 20 known or suspected human carcinogens, we reveal that most agents do not generate distinct mutational signatures or increase mutation burden, with most mutations, including driver mutations, resulting from tissue-specific endogenous processes. We identify signatures resulting from exposure to cobalt and vinylidene chloride and link distinct human signatures (SBS19 and SBS42) with 1,2,3-trichloropropane, a haloalkane and pollutant of drinking water, and find these and other signatures in human tumor genomes. We define the cross-species genomic landscape of tumors induced by an important compendium of agents with relevance to human health.

5.
Nat Commun ; 11(1): 4128, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807809

RESUMO

Individual MHC genotype constrains the mutational landscape during tumorigenesis. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately 30% of cases. Recent studies demonstrated poorer response rates in female and younger patients. Although immune responses differ with sex and age, the role of MHC-based immune selection in this context is unknown. We find that tumors in younger and female individuals accumulate more poorly presented driver mutations than those in older and male patients, despite no differences in MHC genotype. Younger patients show the strongest effects of MHC-based driver mutation selection, with younger females showing compounded effects and nearly twice as much MHC-II based selection. This study presents evidence that strength of immune selection during tumor development varies with sex and age, and may influence the availability of mutant peptides capable of driving effective response to immune checkpoint inhibitor therapy.


Assuntos
Mutação/genética , Neoplasias/genética , Neoplasias/imunologia , Fatores Etários , Alelos , Feminino , Genótipo , Humanos , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Masculino , Fatores Sexuais
7.
Nat Commun ; 11(1): 3096, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32555180

RESUMO

Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and that targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Variações do Número de Cópias de DNA/genética , Epigenômica , Mutação em Linhagem Germinativa/genética , Humanos , Filogenia
8.
Nat Commun ; 11(1): 1917, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317634

RESUMO

The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2nd-3rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the pre-malignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.


Assuntos
Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/genética , Desaminase APOBEC-1/metabolismo , Citidina Desaminase/metabolismo , Análise Mutacional de DNA , Detecção Precoce de Câncer , Exoma , Genética , Centro Germinativo/patologia , Humanos , Modelos Lineares , Antígenos de Histocompatibilidade Menor/metabolismo , Mutação , Proteínas/metabolismo , Edição de RNA , RNA Mensageiro , Análise de Célula Única
9.
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.


Assuntos
Mutação/genética , Neoplasias/genética , Fatores Etários , Sequência de Bases , Exoma/genética , Genoma Humano/genética , Humanos , Análise de Sequência de DNA
10.
Nat Commun ; 11(1): 394, 2020 01 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.


Assuntos
Carcinogênese/efeitos da radiação , Instabilidade Genômica/efeitos da radiação , Neoplasias Induzidas por Radiação/genética , Lesões Experimentais por Radiação/genética , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese/genética , Dano ao DNA/efeitos da radiação , Análise Mutacional de DNA , Relação Dose-Resposta à Radiação , Feminino , Amplificação de Genes/efeitos da radiação , Mutação em Linhagem Germinativa , Humanos , Masculino , Camundongos , Camundongos Knockout , Neoplasias Induzidas por Radiação/patologia , Mutação Puntual/efeitos da radiação , Proteínas Proto-Oncogênicas c-met/genética , Lesões Experimentais por Radiação/patologia , Sequenciamento Completo do Genoma
11.
J Hepatol ; 72(5): 946-959, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31899206

RESUMO

BACKGROUND & AIMS: Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. METHODS: Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens. RESULTS: We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra-/- and major urinary protein-urokinase-type plasminogen activator/Il-17ra-/- mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the 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-17raΔHSC mice (deficient in IL-17RA in hepatic stellate cells). 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 with Il-17raΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D3. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC. CONCLUSIONS: Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC. LAY SUMMARY: IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.

12.
Nat Genet ; 52(1): 74-83, 2020 01.
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.


Assuntos
Adenocarcinoma/secundário , Evolução Clonal , Neoplasias Esofágicas/patologia , Genômica/métodos , Modelos Estatísticos , Adenocarcinoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/secundário , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Sequenciamento Completo do Genoma , Adulto Jovem
13.
Cancer Epidemiol Biomarkers Prev ; 29(3): 599-605, 2020 03.
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.

14.
Blood ; 135(1): 41-55, 2020 01 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.


Assuntos
Biomarcadores Tumorais/genética , Metotrexato/uso terapêutico , Mutagênese/efeitos dos fármacos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , 5'-Nucleotidase/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Análise Mutacional de DNA , Feminino , Seguimentos , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Receptores de Glucocorticoides/genética , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética
15.
Nucleic Acids Res ; 48(4): 1941-1953, 2020 02 28.
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.


Assuntos
Mutagênese/genética , Estresse Oxidativo/genética , Dímeros de Pirimidina/genética , Xeroderma Pigmentoso/genética , Linhagem Celular , Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos da radiação , Replicação do DNA/efeitos da radiação , Humanos , Mutagênese/efeitos da radiação , Mutação/genética , Mutação/efeitos da radiação , Estresse Oxidativo/efeitos da radiação , Dímeros de Pirimidina/efeitos da radiação , Raios Ultravioleta , Sequenciamento Completo do Exoma , Xeroderma Pigmentoso/etiologia
16.
Nat Commun ; 10(1): 5546, 2019 12 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.


Assuntos
Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/métodos , Ipilimumab/uso terapêutico , Neoplasias Bucais/terapia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/induzido quimicamente , Linhagem Celular Tumoral , Modelos Animais de Doenças , Neoplasias de Cabeça e Pescoço/induzido quimicamente , Humanos , Camundongos , Neoplasias Bucais/induzido quimicamente , Tabaco/efeitos adversos
17.
Proc Natl Acad Sci U S A ; 116(45): 22730-22736, 2019 11 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.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , Receptor ErbB-2/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/terapia , Sequenciamento Completo do Exoma , Animais , Linhagem Celular Tumoral , Terapia Combinada , Variações do Número de Cópias de DNA , Feminino , Xenoenxertos , Humanos , Polimorfismo de Nucleotídeo Único , Neoplasias do Colo do Útero/patologia
18.
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
19.
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.

20.
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
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