Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
Nature ; 558(7711): 600-604, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29925948

RESUMO

Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.


Assuntos
Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Insuficiência Pancreática Exócrina/etiologia , Insuficiência Pancreática Exócrina/metabolismo , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologia , Animais , Composição Corporal , Modelos Animais de Doenças , Progressão da Doença , Insuficiência Pancreática Exócrina/patologia , Feminino , Masculino , Camundongos , Neoplasias Pancreáticas/metabolismo
2.
Genet Med ; 21(1): 213-223, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29961768

RESUMO

PURPOSE: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. METHODS: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. RESULTS: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05). CONCLUSION: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.


Assuntos
Adenocarcinoma/genética , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Quebras de DNA de Cadeia Dupla , Intervalo Livre de Doença , Etnicidade/genética , Feminino , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia
3.
Br J Cancer ; 117(12): 1874-1882, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-28982112

RESUMO

BACKGROUND: Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC). METHODS: In 600 patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy. RESULTS: Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all Ptrend<0.01). American Joint Committee on Cancer 8th edition effectively predicted DFS and OS, while minimising model complexity. Lymph node metastases had weaker prognostic value in patients with positive margins and distal resections (both Pinteraction<0.03). Lymph node metastases by AJCC 7th and 8th editions did not predict the likelihood of local disease as the first site of recurrence. CONCLUSIONS: American Joint Committee on Cancer 8th edition LN classification is an effective and practical tool to predict outcomes in patients with resected PDAC. However, the prognostic value of LN metastases is attenuated in patients with positive resection margins and distal pancreatectomies.


Assuntos
Carcinoma Ductal Pancreático/secundário , Excisão de Linfonodo , Linfonodos/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Pancreáticas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/cirurgia , Metástase Linfática , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Neoplasia Residual , Pancreatectomia/métodos , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Modelos de Riscos Proporcionais , Taxa de Sobrevida
4.
Genet Med ; 19(7): 787-795, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28125075

RESUMO

PURPOSE: Implementing cancer precision medicine in the clinic requires assessing the therapeutic relevance of genomic alterations. A main challenge is the systematic interpretation of whole-exome sequencing (WES) data for clinical care. METHODS: One hundred sixty-five adults with metastatic colorectal and lung adenocarcinomas were prospectively enrolled in the CanSeq study. WES was performed on DNA extracted from formalin-fixed paraffin-embedded tumor biopsy samples and matched blood samples. Somatic and germ-line alterations were ranked according to therapeutic or clinical relevance. Results were interpreted using an integrated somatic and germ-line framework and returned in accordance with patient preferences. RESULTS: At the time of this analysis, WES had been performed and results returned to the clinical team for 165 participants. Of 768 curated somatic alterations, only 31% were associated with clinical evidence and 69% with preclinical or inferential evidence. Of 806 curated germ-line variants, 5% were clinically relevant and 56% were classified as variants of unknown significance. The variant review and decision-making processes were effective when the process was changed from that of a Molecular Tumor Board to a protocol-based approach. CONCLUSION: The development of novel interpretive and decision-support tools that draw from scientific and clinical evidence will be crucial for the success of cancer precision medicine in WES studies.Genet Med advance online publication 26 January 2017.


Assuntos
Sequenciamento do Exoma/métodos , Exoma/genética , Medicina de Precisão/métodos , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adulto , Neoplasias Colorretais/genética , Bases de Dados Genéticas , Genômica/métodos , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/genética , Mutação/genética , Estudos Prospectivos , Análise de Sequência de DNA/métodos
5.
Adv Biosyst ; 4(12): e2000203, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33103361

RESUMO

Extracellular vesicles (EVs) represent promising circulating biomarkers for cancers, but their high-throughput analyses in clinical settings prove challenging due to lack of simple, fast, and robust EV assays. Here, a bead-based EV assay detected by flow cytometry is described, which integrates EV capture using microbeads with EV protein analyses by flow cytometry. The assay is fast (<4 h for 48 samples), robust, and compatible with conventional flow cytometry instruments for high-throughput EV analysis. With the method, a panel of pancreatic cancer biomarkers in EVs from plasma samples of pancreatic cancer patients is successfully analyzed. The assay is readily translatable to other biomarkers or cancer types and can be run with standard materials on conventional flow cytometers, making it highly flexible and adaptable to diverse research and clinical needs.


Assuntos
Vesículas Extracelulares , Citometria de Fluxo/métodos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Biotinilação , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Humanos , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo
6.
Cancer Epidemiol Biomarkers Prev ; 29(5): 999-1008, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32321713

RESUMO

BACKGROUND: Pancreatic cancer is the third leading cause of cancer death in the United States, and 80% of patients present with advanced, incurable disease. Risk markers for pancreatic cancer have been characterized, but combined models are not used clinically to identify individuals at high risk for the disease. METHODS: Within a nested case-control study of 500 pancreatic cancer cases diagnosed after blood collection and 1,091 matched controls enrolled in four U.S. prospective cohorts, we characterized absolute risk models that included clinical factors (e.g., body mass index, history of diabetes), germline genetic polymorphisms, and circulating biomarkers. RESULTS: Model discrimination showed an area under ROC curve of 0.62 via cross-validation. Our final integrated model identified 3.7% of men and 2.6% of women who had at least 3 times greater than average risk in the ensuing 10 years. Individuals within the top risk percentile had a 4% risk of developing pancreatic cancer by age 80 years and 2% 10-year risk at age 70 years. CONCLUSIONS: Risk models that include established clinical, genetic, and circulating factors improved disease discrimination over models using clinical factors alone. IMPACT: Absolute risk models for pancreatic cancer may help identify individuals in the general population appropriate for disease interception.


Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Modelos Estatísticos , Neoplasias Pancreáticas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Estados Unidos/epidemiologia
7.
Cancer Epidemiol Biomarkers Prev ; 28(12): 2062-2069, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31533940

RESUMO

BACKGROUND: Pancreatic cancer is associated with development of cachexia, a wasting syndrome thought to limit survival. Few studies have longitudinally quantified peripheral tissues or identified biomarkers predictive of future tissue wasting. METHODS: Adipose and muscle tissue were measured by computed tomography (CT) at diagnosis and 50 to 120 days later in 164 patients with advanced pancreatic cancer. Tissue changes and survival were evaluated by Cox proportional hazards regression. Baseline levels of circulating markers were examined in relation to future tissue wasting. RESULTS: Compared with patients in the bottom quartile of muscle change per 30 days (average gain of 0.8 ± 2.0 cm2), those in the top quartile (average loss of 12.9 ± 4.9 cm2) had a hazard ratio (HR) for death of 2.01 [95% confidence interval (CI), 1.12-3.62]. Patients in the top quartile of muscle attenuation change (average decrease of 4.9 ± 2.4 Hounsfield units) had an HR of 2.19 (95% CI, 1.18-4.04) compared with those in the bottom quartile (average increase of 2.4 ± 1.6 Hounsfield units). Changes in adipose tissue were not associated with survival. Higher plasma branched chain amino acids (BCAA; P = 0.004) and lower monocyte chemoattractant protein-1 (MCP-1; P = 0.005) at diagnosis were associated with greater future muscle loss. CONCLUSIONS: In patients with advanced pancreatic cancer, muscle loss and decrease in muscle density in 2 to 4 months after diagnosis were associated with reduced survival. BCAAs and MCP-1 levels at diagnosis were associated with subsequent muscle loss. IMPACT: BCAAs and MCP-1 levels at diagnosis could identify a high-risk group for future tissue wasting.


Assuntos
Tecido Adiposo/fisiopatologia , Composição Corporal , Músculo Esquelético/fisiopatologia , Neoplasias Pancreáticas/mortalidade , Tomografia Computadorizada por Raios X/métodos , Tecido Adiposo/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
8.
JAMA Oncol ; 4(3): e173420, 2018 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-29098284

RESUMO

IMPORTANCE: Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes. OBJECTIVE: To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection. DESIGN, SETTING, AND PARTICIPANTS: This study analyzed protein expression and DNA alterations for the KRAS, CDKN2A, SMAD4, and TP53 genes by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors in 356 patients with resected pancreatic adenocarcinoma who were treated at the Dana-Farber/Brigham and Women's Cancer Center (October 26, 2002, to May 21, 2012), University of Rochester Medical Center (March 1, 2006, to November 1, 2013), or Stanford Cancer Institute (September 26, 1995, to May 22, 2013). Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HRs) and 95% CIs and adjustment for age, sex, tumor characteristics, institution, and perioperative treatment. Data were collected September 9, 2012, to June 28, 2016, and analyzed December 17, 2016, to March 14, 2017. MAIN OUTCOMES AND MEASURES: The DFS and OS among patients with resected pancreatic adenocarcinoma. RESULTS: Of the 356 patients studied, 191 (53.7%) were men and 165 (46.3%) were women, with a median (interquartile range [IQR]) age of 67 (59.0-73.5) years. Patients with KRAS mutant tumors had worse DFS (median [IQR], 12.3 [6.7 -27.2] months) and OS (20.3 [11.3-38.3] months) compared with patients with KRAS wild-type tumors (DFS, 16.2 [8.9-30.5] months; OS, 38.6 [16.6-63.1] months) and had 5-year OS of 13.0% vs 30.2%. Particularly poor outcomes were identified in patients with KRAS G12D-mutant tumors, who had a median (IQR) OS of 15.3 (9.8-32.7) months. Patients whose tumors lacked CDKN2A expression had worse DFS (median, 11.5 [IQR, 6.2-24.5] months) and OS (19.7 [10.9-37.1] months) compared with patients who had intact CDKN2A (DFS, 14.8 [8.2-30.5] months; OS, 24.6 [14.1-44.6] months). The molecular status of SMAD4 was not associated with DFS or OS, whereas TP53 status was associated only with shorter DFS (HR, 1.33; 95% CI, 1.02-1.75; P = .04). Patients had worse DFS and OS if they had a greater number of altered driver genes. Compared with patients with 0 to 2 altered genes, those with 4 altered genes had worse DFS (HR, 1.79 [95% CI, 1.24-2.59; P = .002]) and OS (HR, 1.38 [95% CI, 0.98-1.94; P = .06]). Five-year OS was 18.4% for patients with 0 to 2 gene alterations, 14.1% for those with 3 alterations, and 8.2% for those with 4 alterations. CONCLUSIONS AND RELEVANCE: Patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma.


Assuntos
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirurgia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Proteínas Proto-Oncogênicas/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Análise Mutacional de DNA/métodos , Feminino , Seguimentos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , Análise de Sobrevida , Resultado do Tratamento
9.
Cancer Discov ; 8(9): 1096-1111, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29903880

RESUMO

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC.Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096-111. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.


Assuntos
Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Variação Genética , Genômica/métodos , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/tratamento farmacológico , Reparo do DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Mutação em Linhagem Germinativa , Recombinação Homóloga , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Medicina de Precisão , Análise de Sequência de RNA/métodos , Sequenciamento do Exoma/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA