viernes, 12 de julio de 2019

IDH1R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response. IDH Mutations


IDH1R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response:

Felipe J. Núñez, Flor M. Mendez, Padma Kadiyala, Mahmoud S. Alghamri, Masha G. Savelieff, Carl Koschmann, Anda-Alexandra Calinescu, Neha Kamran, Rohin Patel, Stephen Carney, Marissa Z. Guo, Maria B. Garcia-Fabiani, Santiago Haase, Marta Edwards, Mats Ljungman, Tingting Qin, Maureen A. Sartor, Rebecca Tagett, Sriram Venneti, Jacqueline Brosnan-Cashman, Alan Meeker, Vera Gorbunova, Lili Zhao, Daniel M. Kremer, Li Zhang, Costas A. Lyssiotis, Lindsey Jones, Cameron J. Herting, James L. Ross, Dolores Hambardzumyan, Shawn Hervey-Jumper, Maria E. Figueroa, Pedro R. Lowenstein, Maria G. Castro
doi: https://doi.org/10.1101/389817
This article is a preprint and has not been peer-reviewed [what does this mean?].

Abstract
One sentence summary Mutant IDH1 acts as a tumor suppressor when co-expressed together with TP53 and ATRX inactivating mutations in glioma, inducing genomic stability, DNA repair and resistance to genotoxic therapies.
Abstract Glioma patients whose tumors carry a mutation in the Isocitrate Dehydrogenase 1 (IDH1R132H) gene are younger at the time of diagnosis and survive longer. The molecular glioma subtype which we modelled, harbors IDH1R132H, tumor protein 53 (TP53) and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss. The impact of IDH1R132H on genomic stability, DNA damage response (DDR) and DNA repair in this molecular glioma subtype is unknown. We discovered that IDH1R132H expression in the genetic context of ATRX and TP53 inactivation: (i) increases median survival (MS), (ii) enhances DDR activity via epigenetic upregulation of Ataxia-telangiectasia mutated (ATM) signaling, and (iii) elicits tumor radioresistance. Pharmacological inhibition of ATM or checkpoint kinase 1 and 2 (CHK1/2), two essential kinases in the DDR pathways, restored tumors’ radiosensitivity. Translation of these findings for mlDH1 glioma patients could significantly improve the therapeutic efficacy of radiotherapy, and thus have a major impact on patient survival.

Introduction
A recurrent mutation in Isocitrate Dehydrogenase 1 (IDH1R132H) is found in 80 % of lower grade gliomas (WHO grade II/III), and in a subset of high grade gliomas (WHO grade IV) (1, 2). Glioma patients whose tumors contain the mutation IDH1R132H survive longer (1, 2). Two main molecular subtypes of glioma, which harbor IDH1R132H, have been identified: i) gliomas expressing IDH1R132H, 1p/19q co-deletion, and TERTpromoter mutations; and ii) gliomas expressing IDH1R132H, mutant TP53, and inactivation of ATRX (2, 3). In spite of a better long term prognosis 50-75% of IDH1R132H containing gliomas undergo malignant transformation over time, becoming WHO grade IV glioblastomas (1, 4).
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IDH mutations in glioblastoma and low-grade glioma

In 2008 whole genome analysis of human glioblastomas led to the discovery of mutations in the active site of isocitrate dehydrogenase 1 (IDH1). Initially, IDH1 mutations affecting the highly conserved arginine (R) residue at codon 132 were found with a frequeny of 12% in WHO grade IV glioblastoma. They occurred especially in secondary glioblastoma and were associated with a significant increase in overall patient survival.

After the discovery of IDH mutations in secondary glioblastoma studies were conducted to verify presence of these mutations in low grade gliomas: Approximately 80% of all WHO grade II–III infiltrating/diffuse gliomas (astrocytomas, oligodendrogliomas,and oligoastrocytomas) and secondary glioblastomas show mutations in IDH1 and to a lesser extent IDH2. In contrast to diffuse gliomas, IDH mutations are very rare or absent in a variety of WHO grade I and II CNS tumors, such as pilocytic astrocytomas, subependymal giant cell tumors, gangliogliomas, ependymomas and pleiomorphic xanthoastrocytomas.

Mutations in IDH1 and IDH2 are considered as strong prognostic marker, independently from the other well-known prognostic factors, and correlate with enhanced patient survival. By far the most common mutation is IDH1 R132, it occurs in roughly 70% of astrocytomas and oligodendroglial tumors.

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