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2.
PLoS Genet ; 15(8): e1008344, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31469826

RESUMO

Pancreatic adenocarcinoma (PC) is a lethal malignancy that is familial or associated with genetic syndromes in 10% of cases. Gene-based surveillance strategies for at-risk individuals may improve clinical outcomes. However, familial PC (FPC) is plagued by genetic heterogeneity and the genetic basis for the majority of FPC remains elusive, hampering the development of gene-based surveillance programs. The study was powered to identify genes with a cumulative pathogenic variant prevalence of at least 3%, which includes the most prevalent PC susceptibility gene, BRCA2. Since the majority of known PC susceptibility genes are involved in DNA repair, we focused on genes implicated in these pathways. We performed a region-based association study using the Mixed-Effects Score Test, followed by leave-one-out characterization of PC-associated gene regions and variants to identify the genes and variants driving risk associations. We evaluated 398 cases from two case series and 987 controls without a personal history of cancer. The first case series consisted of 109 patients with either FPC (n = 101) or PC at ≤50 years of age (n = 8). The second case series was composed of 289 unselected PC cases. We validated this discovery strategy by identifying known pathogenic BRCA2 variants, and also identified SMG1, encoding a serine/threonine protein kinase, to be significantly associated with PC following correction for multiple testing (p = 3.22x10-7). The SMG1 association was validated in a second independent series of 532 FPC cases and 753 controls (p<0.0062, OR = 1.88, 95%CI 1.17-3.03). We showed segregation of the c.4249A>G SMG1 variant in 3 affected relatives in a FPC kindred, and we found c.103G>A to be a recurrent SMG1 variant associating with PC in both the discovery and validation series. These results suggest that SMG1 is a novel PC susceptibility gene, and we identified specific SMG1 gene variants associated with PC risk.

4.
Cancer Cell ; 35(2): 267-282.e7, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30686769

RESUMO

We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice.

6.
Proc Natl Acad Sci U S A ; 115(18): 4767-4772, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29669919

RESUMO

To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of CPB1 and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes (PRSS1, CPA1, CTRC, and SPINK1) in a hospital series of pancreatic cancer cases and controls. Variants in CPB1, CPA1 (encoding carboxypeptidase B1 and A1), and CTRC were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious CPB1 variants, defined as having impaired protein secretion and induction of endoplasmic reticulum (ER) stress in transfected HEK 293T cells, were found in the hospital series of pancreatic cancer cases (5/986, 0.5%) than in controls (0/1,045, P = 0.027). Among familial pancreatic cancer cases, ER stress-inducing CPB1 variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls (P = 0.020), with a combined prevalence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls (P < 0.01). More ER stress-inducing CPA1 variants were also found in the combined set of hospital and familial cases with pancreatic cancer than in controls [7/1,546 vs. 1/2,012; P = 0.025; odds ratio, 9.36 (95% CI, 1.15-76.02)]. Overall, 16 (1%) of 1,579 pancreatic cancer cases had an ER stress-inducing CPA1 or CPB1 variant, compared with 1 of 2,068 controls (P < 0.00001). No other candidate genes had statistically significant differences in variant prevalence between cases and controls. Our study indicates ER stress-inducing variants in CPB1 and CPA1 are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.


Assuntos
Carboxipeptidase B , Carboxipeptidases A , Estresse do Retículo Endoplasmático/genética , Predisposição Genética para Doença , Mutação , Proteínas de Neoplasias , Neoplasias Pancreáticas , Idoso , Idoso de 80 Anos ou mais , Carboxipeptidase B/genética , Carboxipeptidase B/metabolismo , Carboxipeptidases A/genética , Carboxipeptidases A/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
7.
J Genet Couns ; 27(4): 988-995, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29441441

RESUMO

Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic ductal adenocarcinoma (PDAC) may benefit from precision therapies and their relatives should undergo tailored cancer prevention. In this study, we compared strategies to identify BRCA carriers with PDAC. Incident cases of PDAC were prospectively recruited for BRCA sequencing. Probands were evaluated using the National Comprehensive Cancer Network (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines. The probability of each proband carrying a mutation was estimated by surveying genetic counselors and using BRCAPRO. BRCA mutations were detected in 22/484 (4.5%) probands. 152/484 (31.2%) and 16/484 (3.3%) probands met the NCCN and MOHLTC guidelines, respectively. The NCCN guidelines had higher sensitivity than the MOHLTC guidelines (0.864 versus 0.227, P < 0.001) but lower specificity (0.712 versus 0.976, P < 0.001). One hundred and nineteen genetic counselors completed the survey. Discrimination was similar between genetic counselors and BRCAPRO (area-under-the-curve: 0.755 and 0.775, respectively, P = 0.702). Genetic counselors generally overestimated (P = 0.008), whereas BRCAPRO severely underestimated (P < 0.001), the probability that each proband carried a mutation. Our results indicate that the NCCN guidelines and genetic counselors accurately identify BRCA mutations in PDAC, while the MOHLTC guidelines and BRCAPRO should be updated to account for the association between BRCA and PDAC.

8.
Gastroenterology ; 154(3): 719-722.e3, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29074453

RESUMO

We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P = 3.27x10-6; exome-wide statistical significance threshold P < 2.5x10-6). Cases had more rare inactivating variants in DNA repair genes than controls, even after excluding 13 genes known to predispose to pancreatic cancer (adjusted odds ratio, 1.35; P = .045). At the suggestive threshold (P < .001), 6 genes were enriched for rare damaging variants (UHMK1, AP1G2, DNTA, CHST6, FGFR3, and EPHA1) and 7 genes had associations with pancreatic cancer risk, based on the sequence-kernel association test. We confirmed variants in BRCA2 as the most common high-penetrant genetic factor associated with pancreatic cancer and we also identified candidate pancreatic cancer genes. Large collaborations and novel approaches are needed to overcome the genetic heterogeneity of pancreatic cancer predisposition.


Assuntos
Biomarcadores Tumorais/genética , Exoma , Variação Genética , Neoplasias Pancreáticas/genética , Sequenciamento Completo do Exoma , Proteína BRCA2/genética , Estudos de Casos e Controles , Heterogeneidade Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Razão de Chances , Neoplasias Pancreáticas/diagnóstico , Fenótipo , Medição de Risco , Fatores de Risco
9.
Eur J Radiol ; 95: 33-38, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28987689

RESUMO

BACKGROUND: Negative-margin status is a prognostic indicator for long-term survival following curative intent resection for pancreatic adenocarcinoma. Patients at increased risk for positive-margin resections may benefit from neoadjuvant chemotherapy prior to resection. METHODS: We retrospectively analyzed preoperative computed-tomography (CT) scans in 108 consecutive patients that underwent curative intent resection for a resectable pancreatic ductal adenocarcinoma from 2009 to 2016 in two academic hospitals. Two radiologists independently staged the tumor, including tumor location, size, and tumor-to-superior mesenteric/portal vein (SMV/PV) contact. Uni and multivariate analysis were performed to identify independent predictors of an R1 resection. RESULTS: Twenty-nine patients had an R1 resection (26.9%). Tumor size, location, and presence of tumor-to-SMV/PV contact were significantly associated with an R1 resection. In multivariate analysis, the independent parameters associated with resection status were: tumor size (R2=9.7), and tumor location (neck R2=6.6; pancreaticoduodenal interface R2=4.4; uncinate process R2=4.1), but not tumor-to-SMV/PV contact (R2=0.1, p=0.7). A simple CT score was built based on tumor size and location. Patients with an R0 resectability score ≥3, i.e. patients with tumor size ≥30mm (except when tumor location is at the pancreatico-duodenal interface) or patients with tumor size ≥20mm AND tumor located in the uncinate process or neck, were at high-risk of an R1 resection (AUC, 0.82; sensitivity, 79%; specificity, 76%). This score also showed good diagnostic performances for predicting an R1 resection involving the medial resection margin only (AUC, 0.85). CONCLUSIONS: A simple score based on tumor location and size can accurately predict patients at high-risk of an R1 resection.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Carcinoma Ductal Pancreático/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/cirurgia , Adulto , Idoso , Carcinoma Ductal Pancreático/patologia , Estudos Transversais , Feminino , Humanos , Masculino , Margens de Excisão , Veias Mesentéricas/patologia , Veias Mesentéricas/cirurgia , Pessoa de Meia-Idade , Análise Multivariada , Terapia Neoadjuvante , Invasividade Neoplásica , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/cirurgia , Veia Porta/patologia , Veia Porta/cirurgia , Prognóstico , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X
10.
Oncoimmunology ; 6(6): e1321185, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28680757

RESUMO

PTP1B and TC-PTP are highly related protein-tyrosine phosphatases (PTPs) that regulate the JAK/STAT signaling cascade essential for cytokine-receptor activation in immune cells. Here, we describe a novel immunotherapy approach whereby monocyte-derived dendritic cell (moDC) function is enhanced by modulating the enzymatic activities of PTP1B and TC-PTP. To downregulate or delete the activity/expression of these PTPs, we generated mice with PTP-specific deletions in the dendritic cell compartment or used PTP1B and TC-PTP specific inhibitor. While total ablation of PTP1B or TC-PTP expression leads to tolerogenic DCs via STAT3 hyperactivation, downregulation of either phosphatase remarkably shifts the balance toward an immunogenic DC phenotype due to hyperactivation of STAT4, STAT1 and Src kinase. The resulting increase in IL-12 and IFNγ production subsequently amplifies the IL-12/STAT4/IFNγ/STAT1/IL-12 positive autocrine loop and enhances the therapeutic potential of mature moDCs in tumor-bearing mice. Furthermore, pharmacological inhibition of both PTPs improves the maturation of defective moDCs derived from pancreatic cancer (PaC) patients. Our study provides a new advance in the use of DC-based cancer immunotherapy that is complementary to current cancer therapeutics.

11.
Eur J Radiol ; 90: 152-158, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28583627

RESUMO

BACKGROUNDS: Patients with a pancreatic cancer amenable to surgery still have a poor prognosis and high risk of post-operative recurrence. We aimed to assess the value of quantitative imaging biomarkers using computed-tomography (CT) texture analysis to evaluate the pathologic tumor aggressiveness and predict disease-free survival (DFS) in patients with resectable pancreatic adenocarcinoma. METHODS: We retrospectively performed attenuation measurements and texture analysis on the portal-venous phase of the pre-operative CT scan of 99 patients that underwent resection of a pancreatic ductal adenocarcinoma in two university hospitals. Tumor attenuation parameters included: mean attenuation value of the whole tumor (WHOLE-AV), and of the most hypoattenuating area within the tumor (CENTRAL-AV). Tumor heterogeneity parameters included: standard deviation, entropy, skewness, and kurtosis. RESULTS: Tumor attenuation parameters showed significant association with the tumor differentiation grade (CENTRAL-AV, Odds ratio (OR) 0.968, 95% confidence interval (CI) 0.94-0.998) and lymph node invasion (WHOLE-AV, OR 0.886, CI 0.823-0.955). Variables associated with early-recurrence were: lymph node ratio (R2=0.15), kurtosis (R2=0.08), and CENTRAL-AV (R2=0.04). Lymph node ratio (Hazard ratio (HR) 1.02), and CENTRAL-AV (HR 0.98) were independently associated with shorter DFS. Patients with CENTRAL-AV<62 Hounsfield units had a shorter 1-year DFS (35% versus 68%, p=0.004). CONCLUSION: Tumors that are more hypoattenuating on the portal-venous phase on CT scan are potentially more aggressive with higher tumor grade, greater lymph node invasion, and shorter DFS.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Adenocarcinoma/patologia , Adulto , Idoso , Biomarcadores , Carcinoma Ductal Pancreático/patologia , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos
12.
Cancer Res ; 77(16): 4517-4529, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28646019

RESUMO

RAD51D is a key player in DNA repair by homologous recombination (HR), and RAD51D truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating RAD51D variants to cancer predisposition remains uncertain. Using deep sequencing and case-control genotyping studies, we show that in French Canadians, the missense RAD51D variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D-XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D-XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic RAD51D missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense RAD51D variants. Cancer Res; 77(16); 4517-29. ©2017 AACR.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação de Sentido Incorreto , Neoplasias Ovarianas/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/patologia , Linhagem , Polimorfismo de Nucleotídeo Único
14.
Sci Transl Med ; 8(365): 365ra159, 2016 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-27856798

RESUMO

Microtubule-targeting agents (MTAs) are widely used anticancer agents, but toxicities such as neuropathy limit their clinical use. MTAs bind to and alter the stability of microtubules, causing cell death in mitosis. We describe DZ-2384, a preclinical compound that exhibits potent antitumor activity in models of multiple cancer types. It has an unusually high safety margin and lacks neurotoxicity in rats at effective plasma concentrations. DZ-2384 binds the vinca domain of tubulin in a distinct way, imparting structurally and functionally different effects on microtubule dynamics compared to other vinca-binding compounds. X-ray crystallography and electron microscopy studies demonstrate that DZ-2384 causes straightening of curved protofilaments, an effect proposed to favor polymerization of tubulin. Both DZ-2384 and the vinca alkaloid vinorelbine inhibit microtubule growth rate; however, DZ-2384 increases the rescue frequency and preserves the microtubule network in nonmitotic cells and in primary neurons. This differential modulation of tubulin results in a potent MTA therapeutic with enhanced safety.


Assuntos
Antineoplásicos/farmacologia , Lactamas Macrocíclicas/farmacologia , Microtúbulos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Oxazóis/farmacologia , Alcaloides de Vinca/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Dimerização , Genômica , Humanos , Lactamas Macrocíclicas/química , Camundongos , Microscopia Eletrônica , Mitose , Transplante de Neoplasias , Oxazóis/química , Tubulina (Proteína)/química , Vimblastina/análogos & derivados , Vimblastina/química , Vimblastina/farmacologia , Alcaloides de Vinca/química , Vinorelbina
15.
Oncotarget ; 7(47): 77838-77853, 2016 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-27788482

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor. Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) are both precursor lesions that lead to the development of PDAC. Reg family proteins (Reg1A, 1B, 3A/G, 4) are a group of calcium-dependent lectins that promote islet growth in response to inflammation and/or injuries. The aim of this study was to establish a role for Reg proteins in the development of PDAC and their clinical value as biomarkers. We found that Reg1A and Reg3A/G were highly expressed in the ADM tissues by immunohistochemistry. In the 3-dimensional culture of mouse acinar cells, Reg3A promoted ADM formation with concurrent activation of mitogen-acitvated protein kinase. Upregulation of Reg1A and Reg1B levels was observed as benign ductal epithelium progresses from PanIN to invasive PDAC. Patients with PDAC showed significantly higher serum levels of Reg1A and Reg1B than matching healthy subjects. These results were further validated by the quantification of Reg 1A and 1B mRNA levels in the microdissected tissues (22- and 6-fold increases vs. non-tumor tissues). Interestingly, patients with higher levels of Reg1A and 1B exhibited improved survival rate than those with lower levels. Furthermore, tissue expressions of Reg1A, Reg1B, and Reg4 could differentiate metastatic PDAC in the liver from intrahepatic cholangiocarcinoma with 92% sensitivity and 95% specificity. Overall, our results demonstrate the upregulation of Reg proteins during PDAC development. If validated in larger scale, Reg1A and Reg1B could become clinical markers for detecting early stages of PDAC, monitoring therapeutic response, and/or predicting patient's prognosis.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Regulação para Cima , Idoso , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Diagnóstico Diferencial , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Litostatina/sangue , Litostatina/genética , Litostatina/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Associadas a Pancreatite/sangue , Proteínas Associadas a Pancreatite/genética , Proteínas Associadas a Pancreatite/metabolismo , Prognóstico , Sensibilidade e Especificidade , Análise de Sobrevida
16.
Nature ; 538(7625): 378-382, 2016 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-27732578

RESUMO

Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.


Assuntos
Carcinogênese/genética , Carcinogênese/patologia , Rearranjo Gênico/genética , Genoma Humano/genética , Modelos Biológicos , Mutagênese/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Carcinoma in Situ/genética , Cromotripsia , Variações do Número de Cópias de DNA/genética , Progressão da Doença , Evolução Molecular , Feminino , Genes Neoplásicos/genética , Humanos , Masculino , Mitose/genética , Mutação/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Poliploidia , Lesões Pré-Cancerosas/genética
17.
Gastroenterology ; 151(6): 1218-1231, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27578530

RESUMO

BACKGROUND & AIMS: Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets. METHODS: We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 nontumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice. RESULTS: In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly up-regulated and 1166 genes that were significantly down-regulated in PDAC compared with nontumor pancreatic tissues. One gene that was up-regulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit αi2, which has not been previously associated with PDAC. G protein subunit αi2 mediates the effects of dopamine receptor D2 (DRD2) on cyclic adenosine monophosphate signaling; PDAC tissues had a slight but significant increase in DRD2 messenger RNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNA interference knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNA interference knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis. CONCLUSIONS: In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might be tested in patients with pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Receptores de Dopamina D2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/secundário , Estudos de Casos e Controles , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/genética , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Haloperidol/farmacologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Fosforilação/efeitos dos fármacos , Pimozida/farmacologia , RNA Interferente Pequeno , Receptores de Dopamina D2/metabolismo , Transdução de Sinais , Transcriptoma , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Regulação para Cima , eIF-2 Quinase/metabolismo
18.
Cancer Lett ; 370(2): 302-12, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26546047

RESUMO

The genetic basis underlying the majority of hereditary pancreatic adenocarcinoma (PC) is unknown. Since DNA repair genes are widely implicated in gastrointestinal malignancies, including PC, we hypothesized that there are novel DNA repair PC susceptibility genes. As germline DNA repair gene mutations may lead to PC subtypes with selective therapeutic responses, we also hypothesized that there is an overall survival (OS) difference in mutation carriers versus non-carriers. We therefore interrogated the germline exomes of 109 high-risk PC cases for rare protein-truncating variants (PTVs) in 513 putative DNA repair genes. We identified PTVs in 41 novel genes among 36 kindred. Additional genetic evidence for causality was obtained for 17 genes, with FAN1, NEK1 and RHNO1 emerging as the strongest candidates. An OS difference was observed for carriers versus non-carriers of PTVs with early stage (≤IIB) disease. This adverse survival trend in carriers with early stage disease was also observed in an independent series of 130 PC cases. We identified candidate DNA repair PC susceptibility genes and suggest that carriers of a germline PTV in a DNA repair gene with early stage disease have worse survival.


Assuntos
Reparo do DNA/genética , Exoma , Neoplasias Pancreáticas/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiologia , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Quinase 1 Relacionada a NIMA , Neoplasias Pancreáticas/mortalidade , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Fatores de Risco , Análise de Sequência de DNA
19.
Ann Surg Oncol ; 23(7): 2168-75, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26714949

RESUMO

BACKGROUND: Colorectal cancer liver metastases (CRLMs) are potentially curable with resection, but most patients recur and succumb to their disease. Clinical covariates do not account for all outcomes. Circulating tumor cells (CTCs) are prognostic in the primary and metastatic settings of breast, prostate and colorectal cancer (CRC), and evolving evidence supports their role in CRLMs. Our objective was to determine whether CTCs in peripheral (PV) and hepatic venous (HV) compartments are associated with disease-free survival (DFS) and overall survival (OS) post-CRLM resection. METHODS: CTCs were measured by CellSearch assay from intraoperative HV and PV samples from 63 patients who underwent CRLM resection from June 2007 to August 2012 at a single center. DFS and OS were primary endpoints. RESULTS: HV CTCs > 3 were associated with shorter DFS and OS, but not PV CTCs, although no significant difference was found between CTC measurements in the two compartments. By univariate analysis, CRC stage and site, CRLM recurrence, and hepatic capsule invasion were also associated with OS, but only HV CTCs and CRC site were significant by multivariate Cox. Only HV CTCs were associated with DFS by multivariate analysis. Cases with elevated HV CTCs had hepatic vein invasion and lymph node metastases, and were younger with larger tumors. CONCLUSIONS: Elevated HV CTCs are prognostic for DFS and OS following CRLM resection. Clinicopathologic features associated with HV CTCs are identifiable preoperatively and should be considered in CRLM surgical decision making. We found no evidence that PV CTCs are prognostic in this setting.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Hepatectomia/mortalidade , Neoplasias Hepáticas/secundário , Células Neoplásicas Circulantes/patologia , Idoso , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
20.
Cancer Discov ; 6(2): 166-75, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26658419

RESUMO

UNLABELLED: Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types. SIGNIFICANCE: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer.


Assuntos
Carcinoma/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Pancreáticas/genética , Análise de Sequência de DNA/métodos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA2/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Humanos , Mutação Puntual
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