Loss-of-Function Mutations in Calcitonin Receptor (CALCR) Identify Highly Aggressive Glioblastoma with Poor Outcome

Pall, Jagriti and Patil, Vikas and Kumar, Anupam and Kaur, Kavneet and Sarkar, Chitra and Somasundaram, Kumaravel (2018) Loss-of-Function Mutations in Calcitonin Receptor (CALCR) Identify Highly Aggressive Glioblastoma with Poor Outcome. In: CLINICAL CANCER RESEARCH, 24 (6). pp. 1448-1458.

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Abstract

Purpose: Despite significant advances in the understanding of the biology, the prognosis of glioblastoma (GBM) remains dismal. The objective was to carry out whole-exome sequencing (WES) of Indian glioma and integrate with that of TCGA to find clinically relevant mutated pathways. Experimental Design: WES of different astrocytoma samples (n = 42; Indian cohort) was carried out and compared with that of TCGA cohort. An integrated analysis of mutated genes from Indian and TCGA cohorts was carried out to identify survival association of pathways with genetic alterations. Patient-derived glioma stem-like cells, glioma cell lines, and mouse xenograft models were used for functional characterization of calcitonin receptor (CALCR) and establish it as a therapeutic target. Results: A similar mutation spectrum between the Indian cohort and TCGA cohort was demonstrated. An integrated analysis identified GBMs with defective neuroactive ligand-receptor interaction pathway (n = 23; 9.54%) that have significantly poor prognosis (P < 0.0001). Furthermore, GBMs with mutated calcitonin receptor (CALCR) or reduced transcript levels predicted poor prognosis. Exogenously added calcitonin (CT) inhibited various properties of glioma cells and pro-oncogenic signaling pathways in a CALCR-dependent manner. Patient-derived mutations in CALCR abolished these functions with the degree of loss of function negatively correlating with patient survival. WT CALCR, but not the mutant versions, inhibited Ras-mediated transformation of immortalized astrocytes in vitro. Furthermore, calcitonin inhibited patient-derived neurosphere growth and in vivo glioma tumor growth in a mouse model. Conclusions: We demonstrate CT-CALCR signaling axis is an important tumor suppressor pathway in glioma and establish CALCR as a novel therapeutic target for GBM. (C) 2017 AACR.

Item Type:	Journal Article
Publication:	CLINICAL CANCER RESEARCH
Additional Information:	Copy right for this article belong to AMER ASSOC CANCER RESEARCH, 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	16 Apr 2018 20:09
Last Modified:	16 Apr 2018 20:09
URI:	http://eprints.iisc.ac.in/id/eprint/59581

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