DISTINCT COPY NUMBER ALTERATIONS AND INCIDENCE OF CHROMOTHRIPSIS ASSOCIATED WITH GRADE AND PROGNOSIS IN IDH MUTANT AND WILD-TYPE GLIOMAS

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Abstract

BACKGROUND: Both IDH mutated (IDHmut) and wild-type (IDHwt) lower grade gliomas can progress to GBM. However, a detailed study of alterations associated with progression of these molecularly distinct tumor types has not been described. Here we perform an analysis of copy number alterations (CNA) across all grades (Grade II-II and Grade IV) IDHmut vs IDHwt infiltrating gliomas. METHODS: DNA was extracted from 94 patient FFPE glioma samples from 4 clinical and molecular groups: Grade II-III IDHwt (n = 17), Grade II-III IDHmut (n = 28), Grade IV IDHwt (n = 25), and Grade IV IDHmut (n = 24). CNA were detected by molecular inversion probes (OncoScan FFPE Express, Affymetrix) and analyzed with Nexus Copy Number Software (BioDiscovery). GISTIC was used to define deletions and amplifications. Chromothripsis (“chromosomal shattering”) was defined using stringent criteria of at least ten switches of CNA in individual chromosomes. RESULTS: Unsupervised clustering of CNAs demonstrated distinct clusters within IDHmut gliomas that correlated with grade. However, within IDHwt gliomas all grades clustered together regardless of grade, with Chr7 amplification (including EGFR) and loss of Chr10 (including PTEN) seen in most tumors. IDHwt Grade II-III and Grade IV tumors both displayed relatively poor prognosis (median survivals of 65.4 and 37.4 weeks). However, IDHmut gliomas had better survival for all grades (604.3 weeks for Grade II-III and 270.3 weeks for Grade IV). Grade IV IDHmut gliomas were more likely to have gains of 1q25.3 (SMG7, NCF2), 1q32.1 (KIF14, DDX59, BTG2), 6p21.1 (HSP90AB1 and other genes) and loss of 3p21 compared with Grade II-III. Functional analyses showed that IDHwt tumors had more amplifications in receptor tyrosine kinases and their downstream pathways. In terms of novel prognostic markers within IDHmut Grade II-III tumors, multivariate analysis identified loss of estrogen receptor B and loss of 10q26.3 containing part of GLRX3 as poor prognostic factors, and CDKN1C loss as a good prognostic factor. Finally, significantly higher incidence of chromothripsis events were observed in grade IV IDHmut compared to IDHwt. CONCLUSIONS: CNA analysis demonstrated significant differences in molecular ontogeny, progression, and prognosis between IDHwt and IDHmut gliomas, which may serve to further elucidate pathogenesis of these distinct tumor types. Significant CNA increases and increased chromothripsis in grade IV IDHmut support malignant transformation of IDHmut low grade gliomas through accumulation of genomic instability, that results later in partial overlap of CNA alterations that are seen earlier in the development of IDHwt tumors. SECONDARY CATEGORY: Tumor Biology.

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