Focal amplification of FAL1, an oncogenic enhancer lncRNA mapping to chromosome 1q is associated with dysregulated BMI1/p21 axis and an adverse event in intracranial ependymomas

Gain of chromosome 1q locus is a common cytogenetic feature associated with intracranial ependymomas; however, candidate non-coding RNAs on this locus have not been identified. Recent studies have reported somatic copy number alterations for long non coding RNA (lncRNA) FAL1/FALEC residing on chromosome 1q to stabilize BMI1, an epigenetic repressor and PRC1 component, leading with to downregulation of p21/CDKN1A tumor suppressor gene. We aimed to study the role of FAL1 in ependymomas, its association with 1q gain, BMI1/p21 regulatory axis and clinicopathological parameters. Using SNP array analysis (GSE32101), 31% (discovery cohort) and 63.8% (in-house cohort) showed amplification/gain of FAL1 locus with higher prevalence in intracranial tumors. Copy number gain of FAL1 locus was significantly associated with increased FAL1 (p=0.003) and BMI1 (p=0.007) levels, and reduced p21 (p=0.001) expressions. Interestingly, gain of FAL1 locus and FAL1 transcripts did not show any association with 1q gain or RELA fusions. Subcellular localization reported FAL1 to be expressed in nuclear compartment in ependymomas. Chromatin immunoprecipitation-qPCR demonstrated in-vivo binding of BMI1 at p21 promoter locus with BMI1 target genes to be enriched in cell architecture related pathways. A 3-tier survival analysis between FAL1 gain and increased expression levels of FAL1 and BMI1 correlated with poor outcome in our cohort. Ours is the first study demonstrating gain of FAL1 locus and its interplay with the BMI1/p21 axis in intracranial ependymomas. Further studies into this epigenetic regulatory mechanism will unravel novel driver mutations in intracranial ependymomas HighlightsSomatic variations in enhancer long non-coding RNA has been recently attributed for various clinical malignancies including cancers. Gain of 1q locus is a common cytogenetic variation observed in intracranial ependymomas. Our study has demonstrated, focal amplification of enhancer lncRNA mapping to Chromosome 1q, FAL1/FALEC, to be involved in oncogenicity/ progression of ependymomas. Moreover, our data suggests a positive association with BMI1 (a PRC1 component) with FAL1 levels, indicating downregulation of BMI1 target gene involved in cell cycle, p21. Furthermore, a 3-tier prognosis analysis (between FAL1 gain, FAL1 and BMI1 expressions) suggests a negative survival outcome. Our study highlights the importance of somatic variation in non-coding genome with ependymoma survival.