New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted T
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New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies Anja M. Schmitt 1 & Ilaria Marinoni 1 & Annika Blank 1 & Aurel Perren 1
# Springer Science+Business Media New York 2016
Abstract The recent findings on the roles of death-associated protein 6/α-thalassemia/mental retardation X-linked (DAXX/ATRX) in the development of pancreatic neuroendocrine tumors (PanNETs) have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a crossspecies study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs. Keywords Review . Pancreatic neuroendocrine tumor . DAXX/ATRX . Epigenetics . Methylation . Alternative lengthening of telomeres
everolimus and the tyrosine kinase inhibitor sunitinib have been approved for the treatment of PanNETs since 2011, due to the lack of systemic collaboration between pathologists, oncologists, and pharmaceutical industries, it is still not known which subset of patients will respond to these compounds. The recent findings on the roles of DAXX/ATRX in the development of PanNETs have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a crossspecies study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs.
DAXX and ATRX Mutations Introduction Pancreatic neuroendocrine tumors (PanNETs) harbor a significant malignant potential with 50 % of patients dying of their tumor within 10 years [1]. Although the options for medical therapies have increased during the last decade, as yet there is no tailored therapy for individual patients. This is on the one hand due to the fact that PanNETs are genetically heterogenous and do not share many classical pathways of tumorigenesis with their non-endocrine counterparts [2]. On the other hand, although targeted therapies with the mTOR inhibitor * Anja M. Schmitt [email protected]
1
Institute of Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland
The first whole exome sequencing analysis on 68 unselected PanNETs by Jiao et al. confirmed mutations of mTOR pathway genes in 15 % of PanNET, while the MEN1 gene was shown to be mutated in 20 % of them. Importantly, in 40 % of the tumors, the authors found mutations in either one of two Bnew^ genes, DAXX (death-associated protein 6, located at 6p21.3) and ATRX (α-thalassemia/mental retardation X-linked, located at Xq13.1q21.1) [2]. DAXX and ATRX mutations are mutually exclusive and are associated with loss of the respective proteins [2, 3]. Clinically, DAXX/ATRX-mu
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