Capicua (CIC) mutations in gliomas in association with MAPK activation for exposing a potential therapeutic target.
Authors: Darabi Sourat , Xiu Joanne , Magee Daniel , Kesari Santosh , Carrillo Jose Arganda , Aulakh Sonikpreet , Walsh Kyle , Sengupta Soma , Sumrall Ashley Love , Spetzler David , Glantz Michael J. , Korn Wolfgang Michael , Demeure Michael J. 
Published: June 2022

2056

Background: Capicua (CIC) Gene is a tumor suppressor, transcriptional repressor, and a member of the high mobility (HMG)-box protein family. CIC is a negative regulator of MAPK and RTK pathways; inactivating CIC mutations (mut) occur in approximately 40% of oligodendrogliomas (OLIG) and less frequently in other gliomas putatively activating downstream signaling. With a goal to identify potential novel treatment options for various gliomas, we explored key signaling pathways associated with CIC mut. Methods: Consecutive glioma tumors were analyzed using Next-Gen DNA sequencing (NextSeq, 592 genes or NovaSeq, whole-exome), RNA sequencing (NovaSeq, WTS ) and IHC (Caris Life Sciences, Phoenix, AZ). Immune cell fraction was calculated by QuantiSeq; MAPK activation score (MPAS) was evaluated using RNAseq data. A comparison was made using Chi2 or Fisher’s-exact test with correction for multiple-comparison (q) using Benjamini-Hochberg. Results: A total of 196 (3.7%) tumors with CIC mut were seen in 5266 gliomas tumors analyzed, with the highest prevalence seen in OLIG (143 of 285, 50.2%). There was no difference between grade 3 (73 of 142, 51.4%) and grade 2 OLIG (70 of 143, 49%). CIC mut were infrequent in astrocytomas (16 of 829, 1.9%; grade 3, 12/510 or 2.4%; grade 2, 4/261 or 1.5%; grade 1, 0/58). CIC mut were present in glioblastomas (24/2753 or 0.6%), gliosarcomas (1/128 or 0.8%), and other mixed subtypes (12/185 or 6.5%). CIC mut were associated with higher prevalence of IDH1/2 mut (92% in CIC-mut vs. 17% in wild type), MGMT promoter methylation (97% vs. 47%), FUBP1 mut (32% vs. 1%) but lower PTEN mut (1% vs. 25%) and TP53 mut (12% vs. 39%) (all q < 0.05). Significant mutual exclusivity for CIC mut and MAPK pathway drivers observed: EGFR amplification (1.5% vs. 27%) , EGFR mut (0.5% vs. 12.6%), NF1 mut (4% vs. 18%) (all q < 0.05). BRAF mut rate was similar in CIC-mut or wild-type (1% vs. 3%, p = ns). Although associated with a higher tumor mutation burden (cutoff > = 10 mut/MB, 13% vs. 3%), a lower prevalence of PDL1 expression (1% vs. 16%) and lower M1 macrophage infiltration were seen (all q < 0.05). Similar effects were seen when stratifying by oligodendroglial and astrocytic histology. CIC mut were associated with increased MPAS score in OLIG (p = 0.01), particularly when compared to tumors lacking additional MAPK drivers (p = 0.001). This effect was not seen in astrocytic tumors, although EGFR alterations (including CNA, EGFRvIII, EGFR fusion and mut) were independently associated with increased MPAS scores (p < 0.001). Conclusions: CIC mut were frequent in oligodendrogliomas but occurred rarely in other glioma tumors and are associated with favorable prognostic markers. RNA expression analysis suggests CIC mut is associated with MAPK activation in OLIG, as are EGFR alterations in astrocytomas. Targeted inhibition of this pathway in selected gliomas may be a promising therapeutic avenue and should be explored further.