title: Loss of CIC and FUBP1 expressions are potential markers of shorter time to recurrence in oligodendroglial tumors.
abstract: Combined deletion of chromosomes 1p and 19q is a prognostic marker in oligodendroglial tumors. Recent studies in oligodendroglial tumors have unveiled recurrent mutations of CIC (homolog of Drosophila capicua) and FUBP1 (far upstream element binding protein 1) that are located on 19q13 and 1p31, respectively. However, the impact of CIC and FUBP1 mutations on their protein expressions has not been examined. The aims of this study were to correlate the expression patterns of CIC and FUBP1 with their mutation profiles and to evaluate the clinical relevance of these molecular markers in 55 oligodendroglial tumors diagnosed in 47 adult patients. Using direct sequencing, somatic mutations of CIC and FUBP1 were identified in 47% (22/47) and 16% (7/45) of oligodendroglial tumors, respectively. Immunohistochemical analysis revealed loss of CIC or FUBP1 protein expression in 36% (20/55) and 16% (9/55) of oligodendroglial tumors examined. Somatic mutation was significantly associated with absent protein expression for both genes (CIC, P=0.01; FUBP1, P=0.00001). Four tumors with undetectable CIC mutations exhibited absent CIC expression, suggesting that CIC inactivation could be mediated by mechanisms other than mutations and genomic loss. Univariate survival analysis revealed that 1p/19q codeletion was significantly associated with overall survival (P=0.05). Loss of CIC expression was significantly correlated with shorter progression-free survival (P=0.03), whereas CIC alteration (mutation or null expression) with worse overall survival (P=0.05). Absent FUBP1 expression was linked with unfavorable progression-free survival (P=0.02) and overall survival (P=0.01). In 16 tumors with 1p/19q codeletion, CIC mutation was associated with unfavorable survival (P=0.01). There was a correlation between lack of CIC or FUBP1 expression and poor progression-free survival (P=0.004; P=0.0003). No molecular markers showed association with survival in oligodendroglial tumors lacking 1p/19q codeletion. We conclude that absent CIC and FUBP1 expressions are potential markers of shorter time to recurrence and CIC mutation a potential marker of worse prognosis, especially in tumors carrying 1p/19q codeletion.
authors.affiliation: 1] Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China [2] The Chinese University of Hong Kong-Shenzhen Research Institute, Shenzhen, China.
authors.forename: Aden Ka-Yin
authors.initials: AK
authors.lastname: Chan
authors.affiliation: 1] Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China [2] The Chinese University of Hong Kong-Shenzhen Research Institute, Shenzhen, China.
authors.forename: Jesse Chung-Sean
authors.initials: JC
authors.lastname: Pang
authors.affiliation: 1] Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China [2] The Chinese University of Hong Kong-Shenzhen Research Institute, Shenzhen, China.
authors.forename: Nellie Yuk-Fei
authors.initials: NY
authors.lastname: Chung
authors.affiliation: 1] Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China [2] The Chinese University of Hong Kong-Shenzhen Research Institute, Shenzhen, China.
authors.forename: Kay Ka-Wai
authors.initials: KK
authors.lastname: Li
authors.affiliation: Neurosurgery Division, Department of Surgery, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Wai Sang
authors.initials: WS
authors.lastname: Poon
authors.affiliation: Neurosurgery Division, Department of Surgery, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Danny Tat-Ming
authors.initials: DT
authors.lastname: Chan
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Liangfu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: 1] Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China [2] The Chinese University of Hong Kong-Shenzhen Research Institute, Shenzhen, China.
authors.forename: Ho-Keung
authors.initials: HK
authors.lastname: Ng
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D004265:DNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism*; D009837:Oligodendroglioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D016016:Proportional Hazards Models; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C498610:CIC protein, human; D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D004265:DNA Helicases