JOP. J Pancreas (Online) 2014 Mar 10; 15(2):138-139.



Biomarkers in Pancreatic Neuroendocrine Tumors

Highlights from the “2014 ASCO Gastrointestinal Cancers Symposium”.

San Francisco, CA, USA. January 16-18, 2014



Maria Serafeim Theochari1, Konstantinos N Syrigos1, Muhammad Wasif Saif2



1Oncology Unit, Third Department of Medicine, Sotiria General Hospital. Athens, Greece. 2Department of Medicine and Cancer Center, Tufts Medical Center. Boston, MA, USA.




The aim of biomarkers is to identify patients most likely to benefit from a therapeutic strategy. Pancreatic neuroendocrine tumors are rare neoplasms that arise in the endocrine tissues of the pancreas. Pancreatic neuroendocrine tumors represent 3% of primary pancreatic neoplasms and their incidence has risen. The SMAD4 gene is located on chromosome 18q and someday the SMAD4 gene status may be useful for prognostic stratification and therapeutic decision. The cells respond to environmental signals by modulating the expressions of genes contained within the nucleus, when genes are activated are transcribed to generate messenger RNA (mRNA). The examination of multiple expressed genes and proteins provides more useful information for prognostication of individual tumors. Here we summarize and discuss findings presented at the 2014 ASCO Gastrointestinal Cancers Symposium. Anna Karpathakis et al. (Abstract #212) reported data about the role of DNA methylation in gastrointestinal neuroendocrine tumors. Christina Lynn Roland et al. (Abstract #250) looked the impact Of SMAD4 on oncologic outcomes. Bong Kynn Kang et al. (Abstract #251) investigated prognostic biomarker using microRNA array technology.



What We Knew Before the 2014 ASCO Gastrointestinal Cancers Symposium

Pancreatic tumors present many times with advanced disease and limited treatment effect. The most used biomarker is a neurosecretory peptide chromogranin A and is of limited value as a predictor of treatment efficacy. Gene expression profiling is very promising. Changes in biomarkers may be associated with disease progression and response to treatment [1, 2].

Pancreatic neuroendocrine tumor loss by immunohistochemistry and loss of PAX8 is associated to a worse survival. The predictive biomarkers are somatostatin receptors, mammalian target of rapamycin (mTOR) pathway molecule, thymidylate synthase, and activated p-Akt [3].

What We Learned at the 2014 ASCO Gastrointestinal Cancers Symposium

Genome-Wide DNA Methylation Profiling of Gastrointestinal Neuroendocrine Tumors to Identify Hypermethylation of mTOR, Notch Pathways in GI NET Pathways (Abstract #212) [4].

Anna Karpathakis et al. made the first comprehensive analysis of the epigenetic profile and they identify that increasing RASSF1 promoter hypermethylation was associated with higher tumor grade. They also identified methylation of multiple cancer related pathways (including the Wnt, mTOR and Notch pathways) as a feature of hepatic metastases.

Loss of SMAD4 and Effect on Overall Survival in Resected Gastrointestinal Neuroendocrine Tumors (Abstract #250) [5].

Christina Lynn Roland et al. investigated the role of SMAD4 expression and overall survival. It was classified in three categories (negative-low-high). Thirty-three tumors were examined and differences in SMAD4 expression result in important differences in overall survival without statistically significant difference.

MicroRNA 27b as a Prognostic Marker in Pancreatic Neuroendocrine Tumors (Abstract #251) [6].

Bong Kynn Kang et al. used the microRNA array technology to elucidate prognostic biomarker and they found that microRNA 27b would be a prognostic marker of recurrence in resected pancreatic neuroendocrine tumors.


We reported some important abstracts presented at the 2014 ASCO Gastrointestinal Cancers Symposium. The molecular markers are very useful, but we need larger studies. All of the above suggests that sequencing might provide many therapeutic targets or involved pathways for prediction. We must access prognostic and predictive biomarkers. Novel biomarkers must be explored and there are data regarding the potential role. Studies utilizing proteomics and tissue arrays are useful to provide insight into tumor biology. Biomarkers must be discovered to be sensitive and specific. Another era is early diagnosis, as well as circulating cell tumors. Because of the nature of these tumors, well designed studies are needed and promising results of therapy targeting pathways (mTOR and Notch).



Key words Biological Markers; MicroRNAs, Neuroendocrine Tumors; Smad4 Protein

Conflict of interest The authors have no potential conflict of interest

Maria Serafeim Theochari
Oncology Unit
Third Department of Medicine
Mesogion 152
Athens, 11527
Phone: +30.21.0776.3100
Fax: +30-21.0778.8055
E-mail: mtheochari@gmail.com




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2. Hochwald SN, Zee S, Conlon KC, et al. Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol 2002;20:2633-42

3. Duerr EM, Chung DC. Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab 2007; 21:1.

4. Anna Karpathakis A, Harpreet Dibra H, Tiffany Morris T, Dahmane Oukrife D, Christodoulos P Pipinikas CP, Kerra Pearce K, et al. Genome-wide DNA methylation profiling of gastrointestinal neuroendocrine tumors to identify hypermethylation of mTOR, Wnt, and Notch pathways in GI NET pathogenesis. J Clin Oncol 2014; 32(Suppl 3): Abstract 212. http://meetinglibrary.asco.org/content/122597-143

5. Roland CL, Kang Y, Chatterjee D, Estrella J, Rashid A, Lee JE, et al. Loss of SMAD4 and effect on overall survival in resected gastrointestinal neuroendocrine tumors. J Clin Oncol 2014; 32(Suppl 3): Abstract 250. http://meetinglibrary.asco.org/content/122676-143

6. Kang BK, Hwang IK, Lee YS, Kim J, Hwang JH. MicroRNA-27b as a prognostic marker in pancreatic neuroendocrine tumor. J Clin Oncol 2014; 32(Suppl 3): Abstract 251. http://meetinglibrary.asco.org/content/123107-143