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Pancreatic Cancer

Role of Next-Generation Sequencing in Pancreatic Cancer Management

Introduction

Pancreatic cancer (PC) is considered one of the most fatal cancers in the U.S. and other developed countries. The best outcomes and survival rates after treatment are only possible with early detection and treatment before the onset of symptoms. There is a great need to uncover ways to detect PC early to achieve better clinical outcomes. To date, there are no reliable means for the early, pre-symptom detection of PC.

Discovery of non-invasive biomarkers is believed to be a possible answer to the question of early detection. Once early detection is possible, however, more effective, targeted treatments are needed to realize higher cure rates. Research involving next-generation sequencing (NGS) data is providing information that can provide keys to approaches to develop non-invasive biomarkers and novel, effective treatments for PC.

Genetic and Genomic Characterization of Pancreatic Cancer

A step toward unveiling information needed to improve PC diagnostics and treatment is to characterize the genomic changes associated with PC. Yu et al. performed a study to detect mutations in pancreatic juice with the goal to obtain information that may form the basis of a test to detect PC (1). They performed digital NGS to detect low-abundance mutations in the pancreatic juice of patient with PC and non-affected patients (controls). One or more KRAS mutations were detected in a significant sample of pancreatic juice from patients with PC. SMAD4 and TP53 mutations were also noted in a number of samples from patients with PC.

Using torrent semiconductor-based NGS, Amato et al. assessed cancer-associated genes in neoplasms and cystic fluid from patients with PC (2). GNAS, KRAS, and TP53 mutations were detected and higher in neoplastic pancreatic tissue and cystic fluid. Using NGS for the identification of mutations in cystic fluid could potentially improve PC diagnosis.

Liang et al. used NGS to perform whole genome sequencing in order to identify somatic changes in the patients with PC (3). They also performed RNA sequencing to determine if any expression changes correspond to somatic changes. Changes in the KRAS signaling and tumor suppressive pathways were detected. RNA analysis showed changes in genes associated with cancer development, including glycogen synthase kinase 3 beta, BRCA2, TP53, and, BCL3.

Mullër et al. analyzed the coding and non-coding transcriptome of pancreatic and healthy tissue using NGS (4). A number of differentially expressed and regulated RNA species were detected in PC tissue including miRNAs, ncRNAs, snoRNAs, piRNAs, and lncRNAs.  This data can be used in conjunction with mRNA expression data to determine functional information.

Application of NGS in Pancreatic Cancer Diagnostics

Genetic and genomic studies to date have uncovered a wealth of novel information regarding the molecular alterations that are associated with PC. Studies continue to be ongoing to use this and other emerging information to develop sensitive and early diagnostic approaches. Thus far, various specific mutations and expression changes in RNA species have been identified (among other genomic and cellular changes).

Targeted NGS studies, such as that conducted by Amato et al. (2), provide essential data that can be used to develop screening and diagnostic tools for early detection. This will allow the initiation of treatments during disease phases that respond favorably to treatments. Detection of specific mutations found to be associated with PC will result in a degree of sensitivity higher than that obtained with genome-wide analyses.

Targeting circulating tumor DNA with NGS is a means to detect genetic alterations using a blood sample. This liquid biopsy approach will allow the analysis of specific genes already identified as associated with PC. This represents another potential approach to non-invasive early detection of PC and PC development risk (5).  

Pancreatic cancer screening panels harness the information uncovered from NGS genetic and genomic profiling studies. Different companies offer screening panels that target a selection of specific genes already found to be mutated in PC tissues/samples. The genes more commonly targeted using these panels are TP53, BRCA1, BRCA2, and ATM. These panels use NGS to sequence specific genes associated with an increased risk of developing PC. Full sequencing is performed and the results are analyzed for mutations.

NGS and Identification of Therapeutic Targets

Somatic alterations in genes associated with PC are potential targets to develop new therapies or apply therapies already approved by the U.S. Food and Drug Administration (6). The design of highly specific therapies can target mutated genes characterized by NGS. The genetic profiling data gained to date are valuable resources for studies to develop therapies that can be implemented at the earliest detection of PC.

A new clinical trial is being conducted by Karolinska University Hospital in Sweden to obtain drug candidates.  NGS data will be processed with a bioinformatics tool capable of providing evidenced-based drug possibilities. The identified candidates will then be subjected to a medical review (7).

Conclusions

Much work remains necessary to associate PC-associate mutations with processes that can be exploited to design reliable screening and diagnostic tools. The current limitations must be overcome (such as variability of findings across individuals) in order to successfully target the specific alterations that will lead to a change in clinical outcomes. Continued advances in NGS applied to PC, including improved data interpretation, will enable better-informed PC drug discovery efforts.

References

  • Yu J, Sadakari Y, Shindo K, Suenaga M, Brant A, Almario JA, Borges M, Barkley T, Fesharakizadeh S, Ford M, Hruban RH, Shin EJ, Lennon AM, Canto MI, Goggins M. Digital next-generation sequencing identifies low-abundance mutations in pancreatic juice samples collected from the duodenum of patients with pancreatic cancer and intraductal papillary mucinous neoplasms. Gut. 2016 Jul 18.
  • Amato E, Molin MD, Mafficini A, Yu J, Malleo G, Rusev B, Fassan M, Antonello D, Sadakari Y, Castelli P, Zamboni G, Maitra A, Salvia R, Hruban RH, Bassi C, Capelli P, Lawlor RT, Goggins M, Scarpa A. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol. 2014 Jul;233(3):217-27.
  • Liang WS, Craig DW, Carpten J, Borad MJ, Demeure MJ, Weiss GJ, Izatt T, Sinari S, Christoforides A, Aldrich J, Kurdoglu A, Barrett M, Phillips L, Benson H, Tembe W, Braggio E, Kiefer JA, Legendre C, Posner R, Hostetter GH, Baker A, Egan JB, Han H, Lake D, Stites EC, Ramanathan RK, Fonseca R, Stewart AK, Von Hoff D. Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing. PLoS One. 2012;7(10):e43192.
  • Müller S, Raulefs S, Bruns P, Afonso-Grunz F, Plötner A, Thermann R, Jäger C, Schlitter AM, Kong B, Regel I, Roth WK, Rotter B, Hoffmeier K, Kahl G, Koch I, Theis FJ, Kleeff J, Winter P, Michalski CW. Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer. Mol Cancer. 2015 Apr 25;14:94.
  • Takai E, Yachida S. Circulating tumor DNA as a liquid biopsy target for detection of pancreatic cancer. World J Gastroenterol. 2016 Oct 14;22(38):8480-8488.
  • Gagan J, Van Allen EM. Next-generation sequencing to guide cancer therapy. Genome Med. 2015 Jul 29;7(1):80.https://clinicaltrials.gov/ct2/show/NCT02767700

About the Author:

Dr. Stacy Matthews Branch is a biomedical consultant, medical writer, and veterinary medical doctor. She owns Djehuty Biomed Consulting and has published research articles and book chapters in the areas of molecular, developmental, reproductive, forensic, and clinical toxicology. Dr. Matthews Branch received her DVM from Tuskegee University and her PhD from North Carolina State University.
Dr. Branch’s Profile 

Written by Macrogen Corp.

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