Abstract A08: Chromothripsis and gene-specific copy number aberrations associated with mutation of IDH1 in glioma
Authors: Colman Howard , Sato Mariko , Mason Clinton C. , Diefes Kristin , Heathcock Lindsey , Abegglen Lisa , Aldape Ken , Schiffman Joshua D. 
Published: August 2014

Abstract
Background: IDH gene mutation in gliomas is associated with younger age and better survival. IDH1 mutation has also been demonstrated to cause global hypermethylation and G-CIMP phenotype in astrocytes. However, the effects of IDH mutation and hypermethylation on molecular ontogeny and DNA copy number alterations in gliomas remain unknown. Here we describe a detailed analysis of copy number alterations (CNA) comparing IDH mutated (IDHmut) and IDH wild-type (IDHwt) gliomas of different grades.
Method: CNAs were detected by molecular inversion probes (OncoScan FFPE Express, Affymetrix) and analyzed with Nexus Copy Number Software (BioDiscovery). DNA was extracted from 94 patient FFPE glioma samples including Grade II-III IDHwt (n=17) and IDHmut (n=28), and Grade IV: IDHwt (n=25) and IDHmut (n=24). Chromothripsis was determined in individual samples using stringent criteria of at least ten distinct CNAs within a single chromosome.
Results: General analysis of CNAs between IDHmut versus IDHwt grade IV (glioblastoma) samples validated prior observations that IDHwt GBM have high frequencies of Chr7 amplification (including EGFR) and loss of Chr10 (including PTEN). The frequency of these specific alterations in IDHmut grade IV tumors was significantly lower. Other CNAs that were significantly different were gain of 19q12, and loss of 14q11 and 22q13 in IDHwt, and gain of 11q21, 10p11, 8q21, 12p13, 1q23, 11q and loss of 11p15, 3p, and 19q13 in IDHmut. Overall, both IDHwt and IDHmut grade IV tumors demonstrated more CNAs compared with lower grade tumors. Inspection of data from individual samples suggested that a higher number of samples from the grade IV IDHmut demonstrated frequent CNAs within individual chromosomes, indicative of chromothripsis. Using stringent criteria of ten distinct CNAs per chromosome, we found a significantly high incidence of chromothripsis events were observed in Grade IV IDHmut compared to IDHwt (p=0.0374). There was also a trend towards higher incidence of chromothripsis in grade IV versus grade I-III IDHmut tumors, but this did not reach statistical significance. Analysis of CNAs at the p53 locus at 17p13 demonstrated that cases with chromothripsis across all tumor grades had a significantly higher incidence of copy number loss or LOH at this locus compared to cases without chromothripsis (p=0.0368).
Conclusions: CNA analysis showed significant differences in CNAs between IDHwt and IDHmut, indicating significant differences in molecular ontogeny. Significant CNA increases and increased chromothripsis in Grade IV IDHmut gliomas suggests that malignant transformation of low grade gliomas may occur through accumulation of genomic instability and genomic catastrophe. Since IDH mutation is thought to be an early event in gliomagenesis, it is possible that the global hypermethylation and other epigenetic alterations induced by IDH mutation in these tumors is mechanistically related to chromosomal instability and chromothripsis. In addition, higher incidence of LOH and copy number loss at the p53 loci in the cases with chromothripsis suggests a potential cooperative role between IDH1 and p53 in this process. Ongoing studies are aimed at further determining the contribution of p53 and ATRX mutation to this phenomenon.
Citation Format: Howard Colman, Mariko Sato, Clinton C. Mason, Kristin Diefes, Lindsey Heathcock, Lisa Abegglen, Ken Aldape, Joshua D. Schiffman. Chromothripsis and gene-specific copy number aberrations associated with mutation of IDH1 in glioma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A08.