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Pancreatic Neoplasms: HELP
Articles by Spencer Knight
Based on 6 articles published since 2010
(Why 6 articles?)

Between 2010 and 2020, Spencer Knight wrote the following 6 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
1 Article Epigenetic silencing of EYA2 in pancreatic adenocarcinomas promotes tumor growth. 2014

Vincent, Audrey / Hong, Seung-Mo / Hu, Chaoxin / Omura, Noriyuki / Young, Angela / Kim, Haeryoung / Yu, Jun / Knight, Spencer / Ayars, Michael / Griffith, Margaret / Van Seuningen, Isabelle / Maitra, Anirban / Goggins, Michael. ·Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD, USA. ·Oncotarget · Pubmed #24810906.

ABSTRACT: To identify potentially important genes dysregulated in pancreatic cancer, we analyzed genome-wide transcriptional analysis of pancreatic cancers and normal pancreatic duct samples and identified the transcriptional coactivator, EYA2 (Drosophila Eyes Absent Homologue-2) as silenced in the majority of pancreatic cancers. We investigated the role of epigenetic mechanisms of EYA2 gene silencing in pancreatic cancers, performed in vitro and in vivo proliferation and migration assays to assess the effect of EYA2 silencing on tumor cell growth and metastasis formation, and expression analysis to identify genes transcriptionally regulated by EYA2. We found loss of tumoral Eya2 expression in 63% of pancreatic cancers (120/189 cases). Silencing of EYA2 expression in pancreatic cancer cell lines correlated with promoter methylation and histone deacetylation and was reversible with DNA methyltransferase and HDAC inhibitors. EYA2 knockdown in pancreatic cancer cell lines increased cell proliferation. Compared to parental pancreatic cancer cells, pancreatic cancers stably-expressing EYA2 grew more slowly and had fewer metastases in orthotopic models. The transcriptional changes after stable expression of EYA2 in pancreatic cancer cells included induction of genes in the TGFbeta pathway. Epigenetic silencing of EYA2 is a common event in pancreatic cancers and stable expression EYA2 limits the growth and metastases of pancreatic adenocarcinoma.

2 Article Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis. 2014

Kim, Haeryoung / Saka, Burcu / Knight, Spencer / Borges, Michael / Childs, Erica / Klein, Alison / Wolfgang, Christopher / Herman, Joseph / Adsay, Volkan N / Hruban, Ralph H / Goggins, Michael. ·Authors' Affiliations: Departments of Pathology, Medicine, Oncology, Surgery and Radiation Oncology, and Molecular Radiation Sciences, The Sol Goldman Pancreatic Cancer Research Center; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea; and Department of Pathology, Emory University Hospital, Atlanta, Georgia. ·Clin Cancer Res · Pubmed #24486587.

ABSTRACT: PURPOSE: To determine how often loss of ataxia-telangiectasia-mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. EXPERIMENTAL DESIGN: The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. RESULTS: Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27-5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response. CONCLUSIONS: Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection.

3 Article Mutant TP53 in duodenal samples of pancreatic juice from patients with pancreatic cancer or high-grade dysplasia. 2013

Kanda, Mitsuro / Sadakari, Yoshihiko / Borges, Michael / Topazian, Mark / Farrell, James / Syngal, Sapna / Lee, Jeffrey / Kamel, Ihab / Lennon, Anne Marie / Knight, Spencer / Fujiwara, Sho / Hruban, Ralph H / Canto, Marcia Irene / Goggins, Michael. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. ·Clin Gastroenterol Hepatol · Pubmed #23200980.

ABSTRACT: BACKGROUND & AIMS: Imaging tests can identify patients with pancreatic neoplastic cysts but not microscopic dysplasia. We investigated whether mutant TP53 can be detected in duodenal samples of secretin-stimulated pancreatic juice, and whether this assay can be used to screen for high-grade dysplasia and invasive pancreatic cancer. METHODS: We determined the prevalence of mutant TP53 in microdissected pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and invasive adenocarcinomas. TP53 mutations were quantified by digital high-resolution melt-curve analysis and sequencing of secretin-stimulated pancreatic juice samples, collected from duodena of 180 subjects enrolled in Cancer of the Pancreas Screening trials; patients were enrolled because of familial and/or inherited predisposition to pancreatic cancer, or as controls. RESULTS: TP53 mutations were identified in 9.1% of intermediate-grade IPMNs (2 of 22), 17.8% of PanIN-2 (8 of 45), 38.1% of high-grade IPMNs (8 of 21), 47.6% of PanIN-3 (10 of 21), and 75% of invasive pancreatic adenocarcinomas (15 of 20); no TP53 mutations were found in PanIN-1 lesions or low-grade IPMNs. TP53 mutations were detected in duodenal samples of pancreatic juice from 29 of 43 patients with pancreatic ductal adenocarcinoma (67.4% sensitivity; 95% confidence interval, 0.52-0.80) and 4 of 8 patients with high-grade lesions (PanIN-3 and high-grade IPMN). No TP53 mutations were identified in samples from 58 controls or 55 screened individuals without evidence of advanced lesions. CONCLUSIONS: We detected mutant TP53 in secretin-stimulated pancreatic juice samples collected from duodena of patients with high-grade dysplasia or invasive pancreatic cancer. Tests for mutant TP53 might be developed to improve the diagnosis of and screening for pancreatic cancer and high-grade dysplasia. Clinical Trial numbers: NCT00438906 and NCT00714701.

4 Article Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts. 2013

Kanda, Mitsuro / Knight, Spencer / Topazian, Mark / Syngal, Sapna / Farrell, James / Lee, Jeffrey / Kamel, Ihab / Lennon, Anne Marie / Borges, Michael / Young, Angela / Fujiwara, Sho / Seike, Junro / Eshleman, James / Hruban, Ralph H / Canto, Marcia Irene / Goggins, Michael. ·Johns Hopkins Medical Institutions, Department of Pathology, Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, 1550 Orleans Street, Baltimore, MD 21231, USA. ·Gut · Pubmed #22859495.

ABSTRACT: OBJECTIVE: Pancreatic cysts are commonly detected in patients undergoing pancreatic imaging. Better approaches are needed to characterise these lesions. In this study we evaluated the utility of detecting mutant DNA in secretin-stimulated pancreatic juice. DESIGN: Secretin-stimulated pancreatic juice was collected from the duodenum of 291 subjects enrolled in Cancer of the Pancreas Screening trials at five US academic medical centres. The study population included subjects with a familial predisposition to pancreatic cancer who underwent pancreatic screening, and disease controls with normal pancreata, chronic pancreatitis, sporadic intraductal papillary mucinous neoplasm (IPMN) or other neoplasms. Somatic GNAS mutations (reported prevalence ≈ 66% of IPMNs) were measured using digital high-resolution melt-curve analysis and pyrosequencing. RESULTS: GNAS mutations were detected in secretin-stimulated pancreatic juice samples of 50 of 78 familial and sporadic cases of IPMN(s) (64.1%), 15 of 33 (45.5%) with only diminutive cysts (<5 mm), but none of 57 disease controls. GNAS mutations were also detected in five of 123 screened subjects without a pancreatic cyst. Among 97 subjects who had serial pancreatic evaluations, GNAS mutations detected in baseline juice samples predicted subsequent emergence or increasing size of pancreatic cysts. CONCLUSION: Duodenal collections of secretin-stimulated pancreatic juice from patients with IPMNs have a similar prevalence of mutant GNAS to primary IPMNs, indicating that these samples are an excellent source of mutant DNA from the pancreas. The detection of GNAS mutations before an IPMN is visible suggests that analysis of pancreatic juice has the potential to help in the risk stratification and surveillance of patients undergoing pancreatic screening.

5 Article The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. 2012

Pérez-Mancera, Pedro A / Rust, Alistair G / van der Weyden, Louise / Kristiansen, Glen / Li, Allen / Sarver, Aaron L / Silverstein, Kevin A T / Grützmann, Robert / Aust, Daniela / Rümmele, Petra / Knösel, Thomas / Herd, Colin / Stemple, Derek L / Kettleborough, Ross / Brosnan, Jacqueline A / Li, Ang / Morgan, Richard / Knight, Spencer / Yu, Jun / Stegeman, Shane / Collier, Lara S / ten Hoeve, Jelle J / de Ridder, Jeroen / Klein, Alison P / Goggins, Michael / Hruban, Ralph H / Chang, David K / Biankin, Andrew V / Grimmond, Sean M / Anonymous31051 / Wessels, Lodewyk F A / Wood, Stephen A / Iacobuzio-Donahue, Christine A / Pilarsky, Christian / Largaespada, David A / Adams, David J / Tuveson, David A. ·Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge CB2 0RE, UK. ·Nature · Pubmed #22699621.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.

6 Article Genome-wide CpG island profiling of intraductal papillary mucinous neoplasms of the pancreas. 2012

Hong, Seung-Mo / Omura, Noriyuki / Vincent, Audrey / Li, Ang / Knight, Spencer / Yu, Jun / Hruban, Ralph H / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA. ·Clin Cancer Res · Pubmed #22173550.

ABSTRACT: PURPOSE: Intraductal papillary mucinous neoplasms (IPMN) are precursors to infiltrating pancreatic ductal adenocarcinomas. Widespread epigenetic alterations are characteristic of many cancers, yet few studies have systematically analyzed epigenetic alterations of neoplastic precursors. Our goal was to conduct genome-wide CpG island methylation profiling to identify aberrantly methylated loci in IPMNs. EXPERIMENTAL DESIGN: We compared the CpG island methylation profiles of six IPMNs to normal primary pancreatic duct samples using methylation CpG island amplification (MCA) and Agilent CpG island microarray (MCAM) analysis. When selected 13 genes identified as differentially methylated by MCAM for methylation-specific PCR (MSP) analysis in an independent set of IPMNs and normal pancreas samples and conducted expression analysis of selected genes. RESULTS: We identified 2,259 loci as differentially methylated in at least one of six IPMNs including 245 genes hypermethylated in IPMNs with high-grade dysplasia compared with normal pancreatic duct samples. Eleven of 13 genes evaluated by MSP were more commonly methylated in 61 IPMNs than in 43 normal pancreas samples. Several genes (BNIP3, PTCHD2, SOX17, NXPH1, EBF3) were significantly more likely to be methylated in IPMNs with high-grade than with low-grade dysplasia. One gene, SOX17, showed loss of protein expression by immunohistochemistry in 22% (19 of 88) of IPMNs. The most specific marker, BNIP3, was not methylated in any IPMNs with low-grade dysplasia or in normal pancreas samples. CONCLUSIONS: IPMNs undergo extensive aberrant CpG island hypermethylation. The detection of genes selectively methylated in high-grade IPMNs such as BNIP3 may have use in the clinical evaluation of IPMNs.