Alternative Lenghtening of Telomeres; Pancreatic Neuro-Endocrine tumors; Epigenetics; DAXX/ATRX
Marinoni Ilaria, Schmitt Anja, Di Domenico Annunziata (2018), Genomic landscape in gastroenteropancreatic neuroendocrine neoplasms and its usefulness in improving the prognostic evaluation, in Diagnostic Histopathology
Di Domenico Annunziata, Wiedmer Tabea, Marinoni Ilaria, Perren Aurel (2017), Genetic and epigenetic drivers of neuroendocrine tumours (NET)., in Endocrine Related Cancer
Wiederkeher Astrid, Wiedmer Tabea, Pantasis Sophia, Di Domenico Annunziata, Vassella Erik, Schmitt Anja, Perren Aurel (2017), Hypo-methylation mediates chromosomal instability in pancreatic NET., in Endocrine Related Cancer
Schmitt Anja, Marinoni Ilaria, Blank Annika, Perren Aurel (2016), New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies, in Endocrine Pathology
Underlying mechanisms of Pancreatic Neuro-Endocrine tumors (pNETs) formation are still elusive and currently there is no means to pre-select patients for specific treatment based on gene mutations or pathways activation. Cancer cells are characterized by a complex interplay between genetic and epigenetic abnormalities that drive the evolution of the malignancy. Epigenetic influences not only gene expression but also telomeres function as well as genomic stability. Epigenetic of pNETs is poorly understood. Mutations in DAXX (Death associated protein 6) or ATRX (ATR-X gene) with correspondent loss of proteins expression occur in 40% of pNETs. DAXX and ATRX negative tumors show ALT (Alternative Lengthening Telomeres) activation a mechanism for telomeres length maintenance, telomerase independent. We have recently shown that loss of DAXX or ATRX predicts for poor disease outcome and that DAXX/ATRX negative tumors show chromosomal instability. DAXX and ATRX regulate the epigenetic status of the cells by mediating both chromatin structure organization and DNA methylation. Preliminary results obtained in our group indicate that DAXX/ATRX negative tumors show a lower level of global DNA methylation compared to positive ones. I hypothesize that DAXX/ATRX loss in pNETs induces an epigenetic reprogramming affecting gene expression as well as telomeres functions and genomic instability. These epigenetic abnormalities may drive the evolution of this subtype of tumors. In the current proposal I aim to: 1. Describe a specific epigenetic profile of DAXX/ATRX negative and ALT positive tumors2. Identify epigenetically regulated players of DAXX/ATRX negative pNETs development and validate their expression 3. Assess the capacity of the identified candidates to mediate response to anti-tumoral treatment. DNA-methylation arrays will be performed on 50 pNET human samples. Methylation profiles will be integrated with gene, miRNA and LncRNA expression data obtained on 30 samples respectively by gene expression arrays and Nanostring technology. Expression of interesting candidates found to be dysregulated from the comparative analysis will be validated on additional samples by Immunohistochemiestry, qRT-PCR and RNA in situ hybridization. Primary cells derived from pNET patients will be treated with different drugs currently in use for pNETs treatment as well as DNA demethylating agents and when possible with drugs targeting the new identified dysregulated pathways. This project will shed light into pancreatic neuro-endocrine tumorigeneisis mechanisms and may lead to the identification of new important therapeutic options.