gms | German Medical Science

Objective: Alterations of the mitogen-activated protein kinase pathway, e.g. KIAA15149:BRAF fusion transcripts, BRAFV600E or FGFR1 mutations, are hallmark events in tumorigenesis of pilocytic astrocytomas (PA). However, occurrence of fusion transcripts and hotspot mutations in one patient in parallel, have only been reported in a single case yet. We aimed to explore coexistence of hotspot mutations and fusion transcripts and to compare clinical aspects of both groups.

Method: Direct sequencing of 102 primary PA with predetermined fusion transcript status diagnosed from 1998-2013 was performed. Primers were specific for mutational hotspot codons of exon 15 in the BRAF and exons 12 and 14 in the FGFR1 gene.

Results: 58 (57%) females and 44 males (43%) with a median age of 16 years were included. Fusion transcripts were present in 51 of 102 patients (50%). BRAFV600E and FGFR1 mutations were detectable in 9 of 102 (9%) and 9 out of 80 (11%) patients. Supratentorial tumor location was found in 13 of 16 patients (81%) with BRAFV600E or FGFR1 mutations but in 6 of 36 patients (17%) with fusion transcripts (p<0.001). Median age of patients with FGFR1 mutations (38 years) was higher as compared to patients with BRAFV600E (15 years, p=0.014) or fusion transcripts (11 years, p=0.006). Patients with BRAFV600E were younger than individuals with wild type genotype (14 vs. 21 years, p=0.025). Age related effects remained significant after sex- and location-adjusting binary logistic regression analyses (p=0.002; p<0.001 and p=0.033, respectively). No cases of coincidental fusion transcript, BRAFV600E or FGFR1 mutations were found. Dependency and mutually exclusive occurrence of FRGR1 and BRAFV600E hotspot mutations with BRAF rearrangements was shown using Fisher's exact test (p=0.003, each). Along the median follow-up (51 months, 44 patients), no mortality occurred. Recurrence was diagnosed in 9 individuals (20%) with a median progression free survival (PFS) of 44 months. None of the analyzed alterations was related to recurrence or PFS.

Conclusions: Our data confirm FGFR1 mutations as an alternative mechanism for tumorigenesis in adults as they were found more frequently in elderly patients and exclusively in BRAFV600E and fusion transcript wild type individuals. None of the analyzed alterations was prognostic for clinical outcome parameters. Thus, being mutually exclusive, informational gain of conjoined determination of hotspot mutations and fusion transcript is sparse.

Note: This work was supported by the Interdisciplinary Centre for Clinical Research, University of Münster (Ha3/016/11).