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1.
Cell ; 173(2): 355-370.e14, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625052

RESUMO

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.


Assuntos
Células Germinativas/metabolismo , Neoplasias/patologia , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Deleção de Genes , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Células Germinativas/citologia , Mutação em Linhagem Germinativa , Humanos , Perda de Heterozigosidade/genética , Mutação de Sentido Incorreto , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Supressoras de Tumor/genética
2.
Cell ; 163(2): 506-19, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26451490

RESUMO

Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Antígenos CD , Neoplasias da Mama/metabolismo , Caderinas/química , Caderinas/genética , Caderinas/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/metabolismo , Feminino , Fator 3-alfa Nuclear de Hepatócito/química , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Modelos Moleculares , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Oncogênica v-akt/metabolismo , Transcriptoma
3.
Cell ; 158(4): 929-944, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25109877

RESUMO

Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.


Assuntos
Neoplasias/classificação , Neoplasias/genética , Análise por Conglomerados , Humanos , Neoplasias/patologia , Transcriptoma
4.
Cell ; 150(2): 264-78, 2012 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-22817890

RESUMO

Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is "captured" as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.


Assuntos
Evolução Clonal , Leucemia Mieloide Aguda/genética , Mutação , Adulto , Idoso , Análise Mutacional de DNA , Progressão da Doença , Feminino , Estudo de Associação Genômica Ampla , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Recidiva , Pele/metabolismo , Adulto Jovem
5.
Nature ; 534(7605): 55-62, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27251275

RESUMO

Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Genômica , Mutação/genética , Proteômica , Transdução de Sinais , Neoplasias da Mama/classificação , Neoplasias da Mama/enzimologia , Proteínas de Ligação ao Cálcio/deficiência , Proteínas de Ligação ao Cálcio/genética , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Classe I de Fosfatidilinositol 3-Quinases , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Espectrometria de Massas , Anotação de Sequência Molecular , Fosfatidilinositol 3-Quinases/genética , Fosfoproteínas/análise , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Proteína Supressora de Tumor p53/genética , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo , Quinases da Família src/genética , Quinases da Família src/metabolismo
6.
Nature ; 502(7471): 333-339, 2013 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-24132290

RESUMO

The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/ß-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.


Assuntos
Carcinogênese/genética , Mutação/genética , Neoplasias/classificação , Neoplasias/genética , Ciclo Celular/genética , Células Clonais/metabolismo , Células Clonais/patologia , Estudos de Coortes , Reparo do DNA/genética , Humanos , Mutação INDEL/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Modelos Genéticos , Neoplasias/metabolismo , Neoplasias/patologia , Oncogenes/genética , Fosfatidilinositol 3-Quinases/genética , Mutação Puntual/genética , Receptores Proteína Tirosina Quinases/metabolismo , Análise de Sobrevida , Fatores de Tempo
7.
Bioinformatics ; 33(19): 3121-3122, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28582538

RESUMO

SUMMARY: BreakPoint Surveyor (BPS) is a computational pipeline for the discovery, characterization, and visualization of complex genomic rearrangements, such as viral genome integration, in paired-end sequence data. BPS facilitates interpretation of structural variants by merging structural variant breakpoint predictions, gene exon structure, read depth, and RNA-sequencing expression into a single comprehensive figure. AVAILABILITY AND IMPLEMENTATION: Source code and sample data freely available for download at https://github.com/ding-lab/BreakPointSurveyor, distributed under the GNU GPLv3 license, implemented in R, Python and BASH scripts, and supported on Unix/Linux/OS X operating systems. CONTACT: lding@wustl.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Variação Estrutural do Genoma , Software , Éxons , Genoma Viral , Genômica , Análise de Sequência de RNA , Integração Viral , Sequenciamento Completo do Genoma
8.
Nature ; 481(7382): 506-10, 2012 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-22237025

RESUMO

Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.


Assuntos
Evolução Clonal/genética , Genoma Humano/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Células Clonais/efeitos dos fármacos , Células Clonais/metabolismo , Células Clonais/patologia , Dano ao DNA/efeitos dos fármacos , Análise Mutacional de DNA , Genes Neoplásicos/genética , Genoma Humano/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Mutagênese/efeitos dos fármacos , Mutagênese/genética , Recidiva , Reprodutibilidade dos Testes
9.
Nature ; 486(7403): 353-60, 2012 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-22722193

RESUMO

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.


Assuntos
Inibidores da Aromatase/uso terapêutico , Aromatase/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Genoma Humano/genética , Anastrozol , Androstadienos/farmacologia , Androstadienos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Reparo do DNA , Exoma/genética , Éxons/genética , Feminino , Variação Genética/genética , Humanos , Letrozol , MAP Quinase Quinase 4/genética , MAP Quinase Quinase Quinase 1/genética , Mutação/genética , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Receptores de Estrogênio/metabolismo , Resultado do Tratamento , Triazóis/farmacologia , Triazóis/uso terapêutico
10.
Mol Cell Proteomics ; 15(3): 1060-71, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26631509

RESUMO

Improvements in mass spectrometry (MS)-based peptide sequencing provide a new opportunity to determine whether polymorphisms, mutations, and splice variants identified in cancer cells are translated. Herein, we apply a proteogenomic data integration tool (QUILTS) to illustrate protein variant discovery using whole genome, whole transcriptome, and global proteome datasets generated from a pair of luminal and basal-like breast-cancer-patient-derived xenografts (PDX). The sensitivity of proteogenomic analysis for singe nucleotide variant (SNV) expression and novel splice junction (NSJ) detection was probed using multiple MS/MS sample process replicates defined here as an independent tandem MS experiment using identical sample material. Despite analysis of over 30 sample process replicates, only about 10% of SNVs (somatic and germline) detected by both DNA and RNA sequencing were observed as peptides. An even smaller proportion of peptides corresponding to NSJ observed by RNA sequencing were detected (<0.1%). Peptides mapping to DNA-detected SNVs without a detectable mRNA transcript were also observed, suggesting that transcriptome coverage was incomplete (∼80%). In contrast to germline variants, somatic variants were less likely to be detected at the peptide level in the basal-like tumor than in the luminal tumor, raising the possibility of differential translation or protein degradation effects. In conclusion, this large-scale proteogenomic integration allowed us to determine the degree to which mutations are translated and identify gaps in sequence coverage, thereby benchmarking current technology and progress toward whole cancer proteome and transcriptome analysis.


Assuntos
Processamento Alternativo , Neoplasias Mamárias Experimentais/genética , Mutação , Proteômica/métodos , Análise de Sequência de DNA/métodos , Análise de Sequência de RNA/métodos , Animais , Biologia Computacional/métodos , Bases de Dados Genéticas , Feminino , Genoma , Humanos , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Polimorfismo de Nucleotídeo Único , Espectrometria de Massas em Tandem , Transcriptoma
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