High KIT and PDGFRA are associated with shorter patients survival in gastroenteropancreatic neuroendocrine tumors, but mutations are a rare event.

Abstract

PURPOSE:

(1) To test whether in genomewide expression profiling differentially expressed genes were also distinct on the protein level including KIT and PDGFRA (2) to correlate the expression with clinicopathological parameters (3) to identify activating mutations that might be eligible for tyrosine kinase inhibitor therapy by mutational analysis of tumors with high expression.

METHODS:

Gastroenteropancreatic neuroendocrine tumors (GEP NETs) from 119 patients were analyzed for protein expression of ten biomarkers. Mutational analysis of KIT (exon 9, 13, 11 and 17) and PDGFRA (exons 12 and 18) was performed on those samples that showed high protein expression.

RESULTS:

High KIT expression was observed in 13% of all specimens, PDGFRA in 33%, CK19 in 26%, CK7 in 2%, CK20 in 5%, S100 in 6%, CD56 in 25%, Chromogranin in 55%, and Synapthophysin in 80%. High expression of KIT and PDGFRA was significantly correlated with shorter disease-specific survival (P = 0.003, P = 0.018, respectively). In multivariate analysis expression of PDGFRA, radicality of surgical treatment and WHO grading influenced disease-specific 10-year survival independently (P = 0.032, P = 0.001 and P = 0.008, respectively). Mutational analysis of highly expressed specimens (n = 51) reveals a novel mutation of KIT in exon 11 (K558N_V559insP) in a well-differentiated metastatic pancreatic neuroendocrine tumor.

CONCLUSIONS:

High expression of KIT and PDGFRA was significantly correlated with shorter patients survival and could serve as prognostic marker. Mutations of the KIT gene might open new avenues for tyrosine kinase inhibitor therapy in a subset of patients with advanced pancreatic neuroendocrine tumors.

• Authors: Thomas Knösel, Yuan Chen, Annelore Altendorf-Hofmann, Christine Danielczok, Martin Freesmeyer, Utz Settmacher, Christine Wurst, Stefan Schulz, Lin Lin Yang, Iver Petersen
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 138 Issue 3 Pg. 397-403 (Mar 2012) ISSN: 1432-1335 [Electronic] Germany
• PMID: 22160160 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• CD56 Antigen
• Chromogranin A
• Ki-67 Antigen
• NCAM1 protein, human
• S100 Proteins
• Synaptophysin
• Keratins
• Proto-Oncogene Proteins c-kit
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (genetics, metabolism)
• CD56 Antigen (metabolism)
• Chromogranin A (metabolism)
• DNA Mutational Analysis
• Digestive System Neoplasms (genetics, metabolism, mortality, pathology)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Intestinal Neoplasms (metabolism, mortality)
• Kaplan-Meier Estimate
• Keratins (metabolism)
• Ki-67 Antigen (metabolism)
• Male
• Middle Aged
• Mutation
• Neuroendocrine Tumors (genetics, metabolism, mortality, pathology)
• Odds Ratio
• Pancreatic Neoplasms (metabolism, mortality)
• Polymerase Chain Reaction
• Predictive Value of Tests
• Prognosis
• Proto-Oncogene Proteins c-kit (genetics, metabolism)
• Receptor, Platelet-Derived Growth Factor alpha (genetics, metabolism)
• S100 Proteins (metabolism)
• Stomach Neoplasms (metabolism, mortality)
• Synaptophysin (metabolism)
• Up-Regulation