KIAA1549‐BRAF Fusions and IDH Mutations Can Coexist in Diffuse Gliomas of Adults

KIAA1549‐BRAF fusion gene and isocitrate dehydrogenase (IDH) mutations are considered two mutually exclusive genetic events in pilocytic astrocytomas and diffuse gliomas, respectively. We investigated the presence of the KIAA1549‐BRAF fusion gene in conjunction with IDH mutations and 1p/19q loss in 185 adult diffuse gliomas. Moreover BRAFv600E mutation was also screened. The KIAA1549‐BRAF fusion gene was evaluated by reverse‐transcription polymerase chain reaction (RT‐PCR) and sequencing. We found IDH mutations in 125 out 175 cases (71.4%). There were KIAA1549‐BRAF fusion gene in 17 out of 180 (9.4%) cases and BRAFv600E in 2 out of 133 (1.5%) cases. In 11 of these 17 cases, both IDH mutations and the KIAA1549‐BRAF fusion were present, as independent molecular events. Moreover, 6 of 17 cases showed co‐presence of 1p/19q loss, IDH mutations and KIAA1549‐BRAF fusion. Among the 17 cases with KIAA1549‐BRAF fusion gene 15 (88.2%) were oligodendroglial neoplasms. Similarly, the two cases with BRAFv600E mutation were both oligodendroglioma and one had IDH mutations and 1p/19q co‐deletion. Our results suggest that in a small fraction of diffuse gliomas, KIAA1549‐BRAF fusion gene and BRAFv600E mutation may be responsible for deregulation of the Ras‐RAF‐ERK signaling pathway. Such alterations are more frequent in oligodendroglial neoplasm and may be co‐present with IDH mutations and 1p/19q loss.

[1]  Fausto J. Rodriguez,et al.  BRAF Alterations in Primary Glial and Glioneuronal Neoplasms of the Central Nervous System With Identification of 2 Novel KIAA1549: BRAF Fusion Variants , 2012, Journal of neuropathology and experimental neurology.

[2]  Wei Wu,et al.  Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers , 2012, The Journal of pathology.

[3]  L. Garraway,et al.  Detection of KIAA1549-BRAF fusion transcripts in formalin-fixed paraffin-embedded pediatric low-grade gliomas. , 2011, The Journal of molecular diagnostics : JMD.

[4]  Yuchen Jiao,et al.  Mutations in CIC and FUBP1 Contribute to Human Oligodendroglioma , 2011, Science.

[5]  N. Alon,et al.  BRAF-KIAA1549 Fusion Predicts Better Clinical Outcome in Pediatric Low-Grade Astrocytoma , 2011, Clinical Cancer Research.

[6]  Kirsten Schmieder,et al.  Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma , 2011, Acta Neuropathologica.

[7]  C. Miller,et al.  Gone FISHing: Clinical Lessons Learned in Brain Tumor Molecular Diagnostics over the Last Decade , 2011, Brain pathology.

[8]  F. Giangaspero,et al.  Prognostic significance of histological grading, p53 status, YKL-40 expression, and IDH1 mutations in pediatric high-grade gliomas , 2010, Journal of Neuro-Oncology.

[9]  T. Forshew,et al.  MAPK pathway activation and the origins of pediatric low‐grade astrocytomas , 2009, Journal of cellular physiology.

[10]  P. Kleihues,et al.  IDH1 Mutations as Molecular Signature and Predictive Factor of Secondary Glioblastomas , 2009, Clinical Cancer Research.

[11]  T. Shaikh,et al.  Duplication of 7q34 in Pediatric Low‐Grade Astrocytomas Detected by High‐Density Single‐Nucleotide Polymorphism‐Based Genotype Arrays Results in a Novel BRAF Fusion Gene , 2009, Brain pathology.

[12]  Hendrik Witt,et al.  Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma , 2009, Acta Neuropathologica.

[13]  Jing Ma,et al.  Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas , 2009, The Journal of pathology.

[14]  D. Pearson,et al.  Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma , 2009, Oncogene.

[15]  P. Kleihues,et al.  IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. , 2009, The American journal of pathology.

[16]  David T. W. Jones,et al.  Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. , 2008, Cancer research.

[17]  P. Burger,et al.  Frequent Gains at Chromosome 7q34 Involving BRAF in Pilocytic Astrocytoma , 2008, Journal of neuropathology and experimental neurology.

[18]  G. Reifenberger,et al.  BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. , 2008, The Journal of clinical investigation.

[19]  Emmanuel Barillot,et al.  BAC array CGH distinguishes mutually exclusive alterations that define clinicogenetic subtypes of gliomas , 2007, International journal of cancer.

[20]  G. Broggi,et al.  Association of chromosome 10 losses and negative prognosis in oligoastrocytomas , 2002, Annals of neurology.

[21]  R. Mccomb,et al.  Pathology and Genetics of Tumours of the Nervous System , 1998 .

[22]  R. Richardson.  Congenital genetic murine (ch) hydrocephalus , 1985, Child's Nervous System.

[23]  D. Brat,et al.  IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children’s Oncology Group , 2010, Child's Nervous System.

[24]  F. Ducray,et al.  IDH1 and IDH2 mutations in gliomas. , 2009, The New England journal of medicine.