Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses

Jones, Siân; Zhang, Xiaosong; Parsons, D. Williams; Lin, Jimmy; Leary, Rebecca J.; Angenendt, Philipp; Mankoo, Parminder K.; Carter, Hannah; Kamiyama, Hirohiko; Jimeno, Antonio; Hong, Seung‐Mo; Fu, Baojin; Lin, Ming Tseh; Calhoun, Eric S.; Kamiyama, Mihoko; Walter, Kimberly; Nikolskaya, Tatiana; Nikolsky, Yuri; Hartigan, James; Smith, Douglas R.; Hidalgo, Manuel; Leach, Steven D.; Klein, Alison P.; Jaffee, Elizabeth M.; Goggins, Michael; Maitra, Anirban; Iacobuzio‐Donahue, Christine A.; Eshleman, James R.; Kern, Scott E.; Hruban, Ralph H.; Karchin, Rachel; Papadopoulos, Nickolas; Parmigiani, Giovanni; Vogelstein, Bert; Velculescu, Victor E.; Kinzler, Kenneth W.

doi:10.1126/science.1164368

Cited by 3,617 publications

(3,520 citation statements)

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“…It has genetic alterations in 100% of pancreatic cancers [1]. The gene PCYT1B (phosphate cytidylyl transferase 1 choline β ) was identified to be associated with pancreatic cancer survival, which is consistent with the previous work [16].…”

Section: Resultssupporting

confidence: 83%

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Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

Gong

Clarke

2014

BMC Systems Biology

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BackgroundRecent global genomic analyses identified 69 gene sets and 12 core signaling pathways genetically altered in pancreatic cancer, which is a highly malignant disease. A comprehensive understanding of the genetic signatures and signaling pathways that are directly correlated to pancreatic cancer survival will help cancer researchers to develop effective multi-gene targeted, personalized therapies for the pancreatic cancer patients at different stages. A previous work that applied a LASSO penalized regression method, which only considered individual genetic effects, identified 12 genes associated with pancreatic cancer survival.ResultsIn this work, we integrate pathway information into pancreatic cancer survival analysis. We introduce and apply a doubly regularized Cox regression model to identify both genes and signaling pathways related to pancreatic cancer survival.ConclusionsFour signaling pathways, including Ion transport, immune phagocytosis, TGFβ (spermatogenesis), regulation of DNA-dependent transcription pathways, and 15 genes within the four pathways are identified and verified to be directly correlated to pancreatic cancer survival. Our findings can help cancer researchers design new strategies for the early detection and diagnosis of pancreatic cancer.

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Section: Resultssupporting

confidence: 83%

“…The pathway information is biologically important to our understanding of gene regulatory networks and cancer development [1]. The previous work [16] performs gene selection based on the strength of individual genes solely and ignores the information of signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

Gong

Clarke

2014

BMC Systems Biology

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“…Pa03C, Pa02C, Panc10.05, and Panc198 (Pa20C) were obtained from A. Maitra at The Johns Hopkins University (Jones et al ., 2008). All cells were maintained at 37 °C in 5% CO2 and grown in DMEM (Invitrogen, Carlsbad, CA, USA) with 10% serum (Hyclone, Logan, UT, USA).…”

Section: Methodsmentioning

confidence: 99%

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

et al. 2017

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Apurinic/apyrimidinic endonuclease 1/redox factor‐1 (APE1/Ref‐1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer‐related pathways. Because APE1 is essential for cell viability, generation of APE1‐knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been possible. To circumvent this challenge, we utilized single‐cell RNA sequencing to identify differentially expressed genes (DEGs) in relation to APE1 protein levels within the cell. Using a straightforward yet novel statistical design, we identified 2837 genes whose expression is significantly changed following APE1 knockdown. Using this gene expression profile, we identified multiple new pathways not previously linked to APE1, including the EIF2 signaling and mechanistic target of Rapamycin pathways and a number of mitochondrial‐related pathways. We demonstrate that APE1 has an effect on modifying gene expression up to a threshold of APE1 expression, demonstrating that it is not necessary to completely knockout APE1 in cells to accurately study APE1 function. We validated the findings using a selection of the DEGs along with siRNA knockdown and qRT‐PCR. Testing additional patient‐derived pancreatic cancer cells reveals particular genes (ITGA1,TNFAIP2,COMMD7,RAB3D) that respond to APE1 knockdown similarly across all the cell lines. Furthermore, we verified that the redox function of APE1 was responsible for driving gene expression of mitochondrial genes such as PRDX5 and genes that are important for proliferation such as SIPA1 and RAB3D by treating with APE1 redox‐specific inhibitor, APX3330. Our study identifies several novel genes and pathways affected by APE1, as well as tumor subtype specificity. These findings will allow for hypothesis‐driven approaches to generate combination therapies using, for example, APE1 inhibitor APX3330 with other approved FDA drugs in an innovative manner for pancreatic and other cancer treatments.

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“…6,7 Pyrimidine analogs (gemcitabine or 5-fluorouracil (5-FU)) are the most commonly used agents, with gemcitabine demonstrating an improved survival compared with no treatment in CONKO-001, 7 and an improved toxicity profile compared with 5-FU in ESPAC-3. 8 Molecular studies have shown that pancreatic ductal adenocarcinomas contain a high number of gene deletions, mutations, amplifications and rearrangements, 9,10 yet the contribution of these genetic abnormalities to tumor behavior and response to systemic therapy is not well understood. The DNA mismatch repair system is integral to maintaining genomic stability, and mismatch repair deficiency is observed in many malignancies.…”

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confidence: 99%

Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma

et al. 2015

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Deficiencies in DNA mismatch repair have been associated with inferior response to 5-FU in colorectal cancer. Pancreatic ductal adenocarcinoma is similarly treated with pyrimidine analogs, yet the predictive value of mismatch repair status for response to these agents has not been examined in this malignancy. A tissue microarray with associated clinical outcome, comprising 254 resected pancreatic ductal adenocarcinoma patients was stained for four mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Mismatch repair deficiency and proficiency was determined by the absence or presence of uniform nuclear staining in tumor cells, respectively. Cases identified as mismatch repair deficient on the tissue microarray were confirmed by immunohistochemistry on whole slide sections. Of the 265 cases, 78 (29%) received adjuvant treatment with a pyrimidine analog and 41 (15%) showed a mismatch repair-deficient immunoprofile. Multivariable diseasespecific survival in the mismatch repair-proficient cohort demonstrated that adjuvant chemotherapy, regional lymph-node status, gender, and the presence of tumor budding were significant independent prognostic variables (P ≤ 0.04); however, none of the eight clinico-pathologic covariates examined in the mismatch repairdeficient cohort were of independent prognostic significance. Univariable assessment of disease-specific survival revealed an almost identical survival profile for both treated and untreated patients with a mismatch repair-deficient profile, while treatment in the mismatch repair-proficient cohort conferred a greater than 10-month median disease-specific survival advantage over their untreated counterparts (P = 0.0018). In this cohort, adjuvant chemotherapy with a pyrimidine analog conferred no survival advantage to mismatch repairdeficient pancreatic ductal adenocarcinoma patients. Mismatch repair immunoprofiling is a feasible predictive marker in pancreatic ductal adenocarcinoma patients, and further prospective evaluation of this finding is Pancreatic ductal adenocarcinoma is among the deadliest solid cancers, with little improvement in overall survival achieved in the past few decades. 1-3 Lack of effective screening modalities and late presentation with advanced stage disease result in fewer than 20% of patients being eligible for surgical resection. 4 Even in surgically-treated patients, the 5-year survival rate is lower than 20%, 5 highlighting the need for more effective and personalized systemic therapeutic approaches. Adjuvant chemotherapy is considered the standard of care for patients with resectable pancreatic ductal adenocarcinoma. 6,7 Pyrimidine analogs (gemcitabine or 5-fluorouracil (5-FU)) are the most commonly used agents, with gemcitabine demonstrating an improved survival compared with no treatment in 7 and an improved toxicity profile compared with 5-FU in ESPAC-3. 8 Molecular studies have shown that pancreatic ductal adenocarcinomas contain a high number of

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Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses

Cited by 3,617 publications

References 35 publications

Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma

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