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1.
Nat Commun ; 10(1): 3163, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320640

RESUMO

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.


Assuntos
Biomarcadores Tumorais/genética , Melanoma/genética , Mutação Puntual/genética , Quinase 4 Dependente de Ciclina/genética , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Masculino , Melanócitos/patologia , Melanoma/patologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Transdução de Sinais/genética , Telomerase/genética , Sequenciamento Completo do Genoma
2.
BMC Med Genomics ; 12(1): 31, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30717762

RESUMO

BACKGROUND: Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett's oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals. METHODS: In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples. RESULTS: We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples. CONCLUSIONS: The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Esôfago de Barrett/complicações , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Rearranjo Gênico , Adenocarcinoma/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Esofágicas/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Sequenciamento Completo do Genoma
3.
J Invest Dermatol ; 139(8): 1762-1768, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30772300

RESUMO

The benign melanocytic nevus is the most common tumor in humans and rarely transforms into cutaneous melanoma. Elucidation of the nevus genome is required to better understand the molecular steps of progression to melanoma. We performed whole genome sequencing on a series of 14 benign melanocytic nevi consisting of both congenital and acquired types. All nevi had driver mutations in the MAPK signaling pathway, either BRAF V600E or NRAS Q61R/L. No additional definite driver mutations were identified. Somatic mutations in nevi with higher mutation loads showed a predominance of mutational signatures 7a and 7b, consistent with UVR exposure, whereas nevi with lower mutation loads (including all three congenital nevi) had a predominance of the ubiquitous signatures 1 and 5. Two nevi had mutations in promoter regions predicted to bind E26 transformation-specific family transcription factors, as well as subclonal mutations in the TERT promoter. This paper presents whole genome data from melanocytic nevi. We confirm that UVR is involved in the etiology of a subset of nevi. This study also establishes that TERT promoter mutations are present in morphologically benign skin nevi in subclonal populations, which has implications regarding the interpretation of this emerging biomarker in sensitive assays.

4.
Int J Cancer ; 144(5): 1049-1060, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30178487

RESUMO

Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15-30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantly affecting those over 65 years of age. We performed genomic analysis of 50 AYA melanoma patients (onset 10-30 years, median 20); 25 underwent whole genome sequencing (WGS) of both tumor and germline DNA, exome data were retrieved from 12 TCGA AYA cases, and targeted DNA sequencing was conducted on 13 cases. The AYA cases were compared with WGS data from 121 adult cutaneous melanomas. Similar to mature adult cutaneous melanomas, AYA melanomas showed a high mutation burden and mutation signatures of ultraviolet radiation (UVR) damage. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the AYA WGS cohort were double the rates observed in adult melanomas (Q < 6.0 × 10-6 and 0.028, respectively). Furthermore, AYA melanomas contained a higher proportion of non-UVR-related mutation signatures than mature adult melanomas as a proportion of total mutation burden (p = 2.0 × 10-4 ). Interestingly, these non-UVR mutation signatures relate to APOBEC or mismatch repair pathways, and germline variants in related genes were observed in some of these cases. We conclude that AYA melanomas harbor some of the same molecular aberrations and mutagenic insults occurring in older adults, but in different proportions. Germline variants that may have conferred disease susceptibility correlated with somatic mutation signatures in a subset of AYA melanomas.


Assuntos
Predisposição Genética para Doença/genética , Células Germinativas/fisiologia , Melanoma/genética , Mutação/genética , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas B-raf/genética , Sequenciamento Completo do Genoma/métodos , Adulto Jovem
5.
J Infect Dis ; 218(12): 2006-2015, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30099516

RESUMO

Background: Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognized by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk. Methods: Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13858 healthy controls of European decent. Results: The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [OR], 1.24; P = 2.49 × 10-9), HLA-DRB5*0101 (OR, 1.29; P = 2.26 × 10-8), HLA-DRB5*9901 (OR, 0.77; P = 1.90 × 10-9), and HLA-DRB3*0301 (OR, 0.63; P = 4.06 × 10-5). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006). Conclusions: Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.


Assuntos
Predisposição Genética para Doença , Antígenos HLA-C/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Receptores KIR/genética , Neoplasias do Colo do Útero/virologia , Estudos de Casos e Controles , Feminino , Dosagem de Genes , Genótipo , Antígenos HLA-C/imunologia , Papillomavirus Humano 16 , Humanos , Polimorfismo de Nucleotídeo Único , Receptores KIR/imunologia
6.
Bone ; 114: 62-71, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29883787

RESUMO

BACKGROUND: Generalised high bone mass (HBM), associated with features of a mild skeletal dysplasia, has a prevalence of 0.18% in a UK DXA-scanned adult population. We hypothesized that the genetic component of extreme HBM includes contributions from common variants of small effect and rarer variants of large effect, both enriched in an extreme phenotype cohort. METHODS: We performed a genome-wide association study (GWAS) of adults with either extreme high or low BMD. Adults included individuals with unexplained extreme HBM (n = 240) from the UK with BMD Z-scores ≥+3.2, high BMD females from the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) (n = 1055) with Z-scores +1.5 to +4.0 and low BMD females also part of AOGC (n = 900), with Z-scores -1.5 to -4.0. Following imputation, we tested association between 6,379,332 SNPs and total hip and lumbar spine BMD Z-scores. For potential target genes, we assessed expression in human osteoblasts and murine osteocytes. RESULTS: We observed significant enrichment for associations with established BMD-associated loci, particularly those known to regulate endochondral ossification and Wnt signalling, suggesting that part of the genetic contribution to unexplained HBM is polygenic. Further, we identified associations exceeding genome-wide significance between BMD and four loci: two established BMD-associated loci (5q14.3 containing MEF2C and 1p36.12 containing WNT4) and two novel loci: 5p13.3 containing NPR3 (rs9292469; minor allele frequency [MAF] = 0.33%) associated with lumbar spine BMD and 11p15.2 containing SPON1 (rs2697825; MAF = 0.17%) associated with total hip BMD. Mouse models with mutations in either Npr3 or Spon1 have been reported, both have altered skeletal phenotypes, providing in vivo validation that these genes are physiologically important in bone. NRP3 regulates endochondral ossification and skeletal growth, whilst SPON1 modulates TGF-ß regulated BMP-driven osteoblast differentiation. Rs9292469 (downstream of NPR3) also showed some evidence for association with forearm BMD in the independent GEFOS sample (n = 32,965). We found Spon1 was highly expressed in murine osteocytes from the tibiae, femora, humeri and calvaria, whereas Npr3 expression was more variable. CONCLUSION: We report the most extreme-truncate GWAS of BMD performed to date. Our findings, suggest potentially new anabolic bone regulatory pathways that warrant further study.


Assuntos
Densidade Óssea/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Vértebras Lombares/diagnóstico por imagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Vértebras Lombares/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
8.
PLoS One ; 13(1): e0190264, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29320538

RESUMO

Technological innovation and increased affordability have contributed to the widespread adoption of genome sequencing technologies in biomedical research. In particular large cancer research consortia have embraced next generation sequencing, and have used the technology to define the somatic mutation landscape of multiple cancer types. These studies have primarily utilised the Illumina HiSeq platforms. In this study we performed whole genome sequencing of three malignant pleural mesothelioma and matched normal samples using a new platform, the BGISEQ-500, and compared the results obtained with Illumina HiSeq X Ten. Germline and somatic, single nucleotide variants and small insertions or deletions were independently identified from data aligned human genome reference. The BGISEQ-500 and HiSeq X Ten platforms showed high concordance for germline calls with genotypes from SNP arrays (>99%). The germline and somatic single nucleotide variants identified in both sequencing platforms were highly concordant (86% and 72% respectively). These results indicate the potential applicability of the BGISEQ-500 platform for the identification of somatic and germline single nucleotide variants by whole genome sequencing. The BGISEQ-500 datasets described here represent the first publicly-available cancer genome sequencing performed using this platform.


Assuntos
Genoma Humano , Células Germinativas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação INDEL , Polimorfismo de Nucleotídeo Único
9.
J Pathol ; 244(4): 460-468, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29344954

RESUMO

Mixed ductal-lobular carcinomas (MDLs) show both ductal and lobular morphology, and constitute an archetypal example of intratumoural morphological heterogeneity. The mechanisms underlying the coexistence of these different morphological entities are poorly understood, although theories include that these components either represent 'collision' of independent tumours or evolve from a common ancestor. We performed comprehensive clinicopathological analysis of a cohort of 82 MDLs, and found that: (1) MDLs more frequently coexist with ductal carcinoma in situ (DCIS) than with lobular carcinoma in situ (LCIS); (2) the E-cadherin-catenin complex was normal in the ductal component in 77.6% of tumours; and (3) in the lobular component, E-cadherin was almost always aberrantly located in the cytoplasm, in contrast to invasive lobular carcinoma (ILC), where E-cadherin is typically absent. Comparative genomic hybridization and multiregion whole exome sequencing of four representative cases revealed that all morphologically distinct components within an individual case were clonally related. The mutations identified varied between cases; those associated with a common clonal ancestry included BRCA2, TBX3, and TP53, whereas those associated with clonal divergence included CDH1 and ESR1. Together, these data support a model in which separate morphological components of MDLs arise from a common ancestor, and lobular morphology can arise via a ductal pathway of tumour progression. In MDLs that present with LCIS and DCIS, the clonal divergence probably occurs early, and is frequently associated with complete loss of E-cadherin expression, as in ILC, whereas, in the majority of MDLs, which present with DCIS but not LCIS, direct clonal divergence from the ductal to the lobular phenotype occurs late in tumour evolution, and is associated with aberrant expression of E-cadherin. The mechanisms driving the phenotypic change may involve E-cadherin-catenin complex deregulation, but are yet to be fully elucidated, as there is significant intertumoural heterogeneity, and each case may have a unique molecular mechanism. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Carcinoma de Mama in situ/patologia , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Neoplasias Complexas Mistas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Antígenos CD/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma de Mama in situ/química , Carcinoma de Mama in situ/genética , Neoplasias da Mama/química , Neoplasias da Mama/genética , Caderinas/análise , Caderinas/genética , Carcinoma Intraductal não Infiltrante/química , Carcinoma Intraductal não Infiltrante/genética , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Progressão da Doença , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Neoplasias Complexas Mistas/química , Neoplasias Complexas Mistas/genética , Fenótipo , Sequenciamento Completo do Exoma
11.
PLoS Genet ; 13(8): e1006866, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28806749

RESUMO

A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA-B/genética , Cadeias HLA-DRB1/genética , Neoplasias do Colo do Útero/genética , Alelos , Estudos de Casos e Controles , Feminino , Técnicas de Genotipagem , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Complexo Principal de Histocompatibilidade , Papillomaviridae , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/virologia
12.
Nature ; 545(7653): 175-180, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-28467829

RESUMO

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.


Assuntos
Genoma Humano/genética , Melanoma/genética , Mutação/genética , DNA Helicases/genética , GTP Fosfo-Hidrolases/genética , Genes p16 , Humanos , Melanoma/classificação , Proteínas de Membrana/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Neurofibromatose 1/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Fatores de Processamento de RNA/genética , Transdução de Sinais/efeitos dos fármacos , Telomerase/genética , Telômero/genética , Proteína Supressora de Tumor p53/genética , Raios Ultravioleta/efeitos adversos , Proteína Nuclear Ligada ao X
13.
Nature ; 543(7643): 65-71, 2017 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-28199314

RESUMO

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.


Assuntos
Carcinoma Neuroendócrino/genética , Genoma Humano/genética , Genômica , Neoplasias Pancreáticas/genética , Sequência de Bases , Proteínas de Ligação a Calmodulina/genética , Montagem e Desmontagem da Cromatina/genética , Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , DNA Glicosilases/genética , Análise Mutacional de DNA , Reparo do DNA/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Serina-Treonina Quinases TOR/metabolismo , Telômero/genética , Telômero/metabolismo
14.
Gastroenterology ; 152(1): 68-74.e2, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27856273

RESUMO

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/genética , Reparo de Erro de Pareamento de DNA/genética , Mutação , Neoplasias Pancreáticas/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Genoma , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
15.
Nature ; 531(7592): 47-52, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26909576

RESUMO

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-ß, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.


Assuntos
Genes Neoplásicos/genética , Genoma Humano/genética , Genômica , Mutação/genética , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Ductal Pancreático/classificação , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Metilação de DNA , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Fator 3-beta Nuclear de Hepatócito/genética , Fator 3-gama Nuclear de Hepatócito/genética , Histona Desmetilases/genética , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Proteínas Nucleares/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Receptores Citoplasmáticos e Nucleares/genética , Análise de Sobrevida , Transativadores/genética , Fatores de Transcrição/genética , Transcrição Genética , Transcriptoma , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Proteínas de Peixe-Zebra
17.
J Pathol ; 237(3): 363-78, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26172396

RESUMO

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2) = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Análise Mutacional de DNA , Ativação Enzimática , Amplificação de Genes , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Ligantes , Terapia de Alvo Molecular , Mutação , Fenótipo , Fosforilação , Medicina de Precisão , Valor Preditivo dos Testes , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Receptor ErbB-4/genética , Receptor ErbB-4/metabolismo , Microambiente Tumoral
18.
Nature ; 521(7553): 489-94, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-26017449

RESUMO

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Genoma Humano/genética , Neoplasias Ovarianas/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Estudos de Coortes , Ciclina E/genética , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Metilação de DNA , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Genes da Neurofibromatose 1 , Mutação em Linhagem Germinativa/genética , Humanos , Mutagênese/genética , Proteínas Oncogênicas/genética , Neoplasias Ovarianas/tratamento farmacológico , PTEN Fosfo-Hidrolase/genética , Regiões Promotoras Genéticas/genética , Proteína do Retinoblastoma/genética
19.
PLoS One ; 10(5): e0126911, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25965996

RESUMO

Genetic variation modulates gene expression transcriptionally or post-transcriptionally, and can profoundly alter an individual's phenotype. Measuring allelic differential expression at heterozygous loci within an individual, a phenomenon called allele-specific expression (ASE), can assist in identifying such factors. Massively parallel DNA and RNA sequencing and advances in bioinformatic methodologies provide an outstanding opportunity to measure ASE genome-wide. In this study, matched DNA and RNA sequencing, genotyping arrays and computationally phased haplotypes were integrated to comprehensively and conservatively quantify ASE in a single human brain and liver tissue sample. We describe a methodological evaluation and assessment of common bioinformatic steps for ASE quantification, and recommend a robust approach to accurately measure SNP, gene and isoform ASE through the use of personalized haplotype genome alignment, strict alignment quality control and intragenic SNP aggregation. Our results indicate that accurate ASE quantification requires careful bioinformatic analyses and is adversely affected by sample specific alignment confounders and random sampling even at moderate sequence depths. We identified multiple known and several novel ASE genes in liver, including WDR72, DSP and UBD, as well as genes that contained ASE SNPs with imbalance direction discordant with haplotype phase, explainable by annotated transcript structure, suggesting isoform derived ASE. The methods evaluated in this study will be of use to researchers performing highly conservative quantification of ASE, and the genes and isoforms identified as ASE of interest to researchers studying those loci.


Assuntos
DNA/análise , Perfilação da Expressão Gênica/métodos , RNA/análise , Análise de Sequência de RNA/métodos , Desequilíbrio Alélico , Encéfalo/metabolismo , Humanos , Fígado/metabolismo , Polimorfismo de Nucleotídeo Único , Isoformas de RNA , Análise de Sequência de DNA/métodos
20.
Nature ; 518(7540): 495-501, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25719666

RESUMO

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.


Assuntos
Análise Mutacional de DNA , Genoma Humano/genética , Genômica , Mutação/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Reparo do DNA/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Marcadores Genéticos/genética , Instabilidade Genômica/genética , Genótipo , Humanos , Camundongos , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/tratamento farmacológico , Platina/farmacologia , Mutação Puntual/genética , Inibidores de Poli(ADP-Ribose) Polimerases , Ensaios Antitumorais Modelo de Xenoenxerto
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