Abstract 1919: Mutation analysis and prognostic relevance of CIC and FUBP1 in oligodendroglial tumors.
Authors: Pang Jesse C. , Chan Aden K. , Chung Nellie Y. , Li Kay , Poon Wai Sang , Ng Ho-Keung 
Published: August 2014

Abstract
Oligodendroglial tumors (OTs) are a major subtype of glioma. They are characterized by IDH mutation and a combined deletion of chromosomes 1p and 19q. OT is an interesting entity in neuro-oncology due to the strong association of 1p/19q codeletion with favorable prognosis and chemosensitivity. Although the mechanism underlying the predictive power of 1p/19q codeletion in prognosis and treatment response is not known, chromosomes 1p and 19q likely contain OT-related genes. Recent exomic sequencing study in OTs revealed two novel mutated genes, CIC and FUBP1, that map to 19q13 and 1p31, respectively. The aims of this study were to (1) determine the incidences of 1p/19q codeletion and mutations of IDH, CIC and FUBP1, and (2) evaluate the clinical relevance of these molecular aberrations in 55 OTs diagnosed at our hospital. Our results showed that somatic mutations of CIC and FUBP1 occurred in 47% and 15% of OTs examined. CIC mutations included 57% indels, 39% missense mutations and 4% nonsense mutation. Missense mutations in CIC were localized to the high-mobility group domain and the C1 motif with repressor activity. More than 75% of missense mutations were predicted to confer damaging effects on cic function. FUBP1 mutations included 3 indels, 3 splicing alterations and 1 nonsense mutation. Six of 7 FUBP1-mutated tumors were concurrently mutated in CIC. 1p/19q codeletion and IDH mutation were observed respectively in 44% and 91% of OTs examined. About 60% of CIC-mutated OTs also showed 1p/19q codeletion, suggesting that, at least in this tumor subset, CIC might act as a candidate tumor suppressor. Follow-up data were available for 44 patients. Survival analysis revealed correlation of tumor grade and patient age of &lt;45 years with better overall survival (OS) (P=0.005 and P=0.002, respectively) and a strong trend of 1p/19q codeletion toward longer survival (P=0.053), but lack of prognostic significance with IDH mutation. Controlling for 1p/19q codeletion, patients whose tumors carrying CIC wild-type showed a longer survival (median OS was not yet reached) than those with CIC mutant (median OS=117 months; P=0.029). In fact, patients whose tumors harboring 1p/19q codeletion and CIC mutation showed survival distribution comparable with those without 1p/19q codeletion. CIC mutation seemed to have increased the aggressiveness of 1p/19q-codeleted tumors. In our cohort, tumors with 1p/19q codeletion and CIC wild-type exhibited the longest survival among all OTs examined. Multivariate analysis, however, showed that only tumor grade, patient age of &lt;45 years and 1p/19q codeletion were independent prognostic factors. In conclusion, our study suggests that CIC and FUBP1 are potential tumor suppressor genes in OTs and that CIC mutation may sub-stratify 1p/19q-codeleted tumors into prognostic groups. Further study with larger sample size is needed to validate our findings.
Citation Format: Jesse C. Pang, Aden K. Chan, Nellie Y. Chung, Kay Li, Wai Sang Poon, Ho-Keung Ng. Mutation analysis and prognostic relevance of CIC and FUBP1 in oligodendroglial tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1919. doi:10.1158/1538-7445.AM2013-1919