Dataset Information

Genetic Tracing of Clonal Expansion and Progression of Pancreatic Ductal Adenocarcinoma: A Case Report and Multi-Region Sequencing Analysis.

ABSTRACT: Pancreatobiliary tumors frequently contain multiple malignant and precancerous lesions; however, the origin of the driver mutations and the mechanisms that underlie the generation of distinct clones within an organ field remain unclear. Herein, we describe a 76-year-old male suffering from moderately differentiated adenocarcinomas of the pancreas that primarily involved the distal bile duct and multiple "dispersing" invasive lesions in the pancreatic head. The patient underwent pylorus-preserving pancreaticoduodenectomy with superior mesenteric vein resection, and targeted sequencing of 18 genes associated with pancreatic tumorigenesis and immunohistochemical analysis of RNF43 and ARID1A were performed on each tumor compartment, including the invasive and non-invasive areas. Multi-region sequencing revealed shared KRAS and TGFBR1 mutations in all invasive foci, including those involving the distal bile duct. Distinct KRAS variants were found to be present in other non-continuous and non-invasive lesions in the pancreas. Intraductal lesions with KRAS G12D and RNF43 V50R mutations were evident in the main pancreatic duct. This appeared to be a founder clone, given that the mutation profile was common to the invasive foci as well as the additional high-grade dysplasia harboring ARID1A mutations, thereby suggesting a clonal branch-off during tumor evolution. In addition, we also observed independent intraductal papillary mucinous neoplasms with KRAS G12V and GNAS R201H mutations. Our theory, learned from this patient, was that lesions skipped dissemination and wide-spread movement potentially through the pancreatic ductal system as a process of pancreatic cancer development.

SUBMITTER: Tachibana S

PROVIDER: S-EPMC7280449 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Genetic Tracing of Clonal Expansion and Progression of Pancreatic Ductal Adenocarcinoma: A Case Report and Multi-Region Sequencing Analysis.

Tachibana Shion S Mizukami Yusuke Y Ono Yusuke Y Sugiyama Yuya Y Okada Tetsuhiro T Kitazaki Arisa A Sasajima Junpei J Tominaga Motoya M Sakamoto Jun J Kimura Keisuke K Omori Yuko Y Furukawa Toru T Kimura Taichi T Tanaka Shinya S Nagashima Kazuo K Karasaki Hidenori H Ohta Tomoyuki T Okumura Toshikatsu T

Frontiers in oncology 20200602

Pancreatobiliary tumors frequently contain multiple malignant and precancerous lesions; however, the origin of the driver mutations and the mechanisms that underlie the generation of distinct clones within an organ field remain unclear. Herein, we describe a 76-year-old male suffering from moderately differentiated adenocarcinomas of the pancreas that primarily involved the distal bile duct and multiple "dispersing" invasive lesions in the pancreatic head. The patient underwent pylorus-preservin ...[more]

PMID: 32582528

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Project description:Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the "hallmarks of cancer." Their expression is dysregulated in cancer, and they are "misused" to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same "profibrotic" ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs.

Project description:Background:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors. The rapid progression of PDAC results in an advanced stage of patients when diagnosed. However, the dynamic molecular mechanism underlying PDAC progression remains far from clear. Methods:The microarray GSE62165 containing PDAC staging samples was obtained from Gene Expression Omnibus and the differentially expressed genes (DEGs) between normal tissue and PDAC of different stages were profiled using R software, respectively. The software program Short Time-series Expression Miner was applied to cluster, compare, and visualize gene expression differences between PDAC stages. Then, function annotation and pathway enrichment of DEGs were conducted by Database for Annotation Visualization and Integrated Discovery. Further, the Cytoscape plugin DyNetViewer was applied to construct the dynamic protein-protein interaction networks and to analyze different topological variation of nodes and clusters over time. The phosphosite markers of stage-specific protein kinases were predicted by PhosphoSitePlus database. Moreover, survival analysis of candidate genes and pathways was performed by Kaplan-Meier plotter. Finally, candidate genes were validated by immunohistochemistry in PDAC tissues. Results:Compared with normal tissues, the total DEGs number for each PDAC stage were 994 (stage I), 967 (stage IIa), 965 (stage IIb), 1027 (stage III), 925 (stage IV), respectively. The stage-course gene expression analysis showed that 30 distinct expressional models were clustered. Kyoto Encyclopedia of Genes and Genomes analysis indicated that the up-regulated DEGs were commonly enriched in five fundamental pathways throughout five stages, including pathways in cancer, small cell lung cancer, ECM-receptor interaction, amoebiasis, focal adhesion. Except for amoebiasis, these pathways were associated with poor PDAC overall survival. Meanwhile, LAMA3, LAMB3, LAMC2, COL4A1 and FN1 were commonly shared by these five pathways and were unfavorable factors for prognosis. Furthermore, by constructing the stage-course dynamic protein interaction network, 45 functional molecular modules and 19 nodes were identified as featured regulators for all PDAC stages, among which the collagen family and integrins were considered as two main regulators for facilitating aggressive progression. Additionally, the clinical relevance analysis suggested that the stage IV featured nodes MLF1IP and ITGB4 were significantly correlated with shorter overall survival. Moreover, 15 stage-specific protein kinases were identified from the dynamic network and CHEK1 was particularly activated at stage IV. Experimental validation showed that MLF1IP, LAMA3 and LAMB3 were progressively increased from tumor initiation to progression. Conclusions:Our study provided a view for a better understanding of the dynamic landscape of molecular interaction networks during PDAC progression and offered potential targets for therapeutic intervention.

Dataset Information

Genetic Tracing of Clonal Expansion and Progression of Pancreatic Ductal Adenocarcinoma: A Case Report and Multi-Region Sequencing Analysis.

Publications

Genetic Tracing of Clonal Expansion and Progression of Pancreatic Ductal Adenocarcinoma: A Case Report and Multi-Region Sequencing Analysis.

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