ABSTRACT
Lipomas are benign fatty tumors with a high prevalence rate, mostly found in adults but have a good prognosis. Until now, reason for lipoma occurrence not been identified. We performed whole exome sequencing to define the mutational spectrum in ten lipoma patients along with their matching control samples. We presented genomic insight into the development of lipomas, the most common benign tumor of soft tissue. Our analysis identified 412 somatic variants including missense mutations, splice site variants, frameshift indels, and stop gain/lost. Copy number variation analysis highlighted minor aberrations in patients. Kinase genes and transcriptions factors were among the validated mutated genes critical for cell proliferation and survival. Pathway analysis revealed enrichment of calcium, Wnt and phospholipase D signaling in patients. In conclusion, whole exome sequencing in lipomas identified mutations in genes with a possible role in development and progression of lipomas.
Subject(s)
Cell Proliferation/genetics , DNA Copy Number Variations/genetics , Exome Sequencing , Lipoma/genetics , Adult , Aged , Codon, Nonsense/genetics , Exome/genetics , Female , Frameshift Mutation/genetics , Humans , INDEL Mutation/genetics , Lipoma/pathology , Male , Middle Aged , Mutation, Missense/genetics , Phosphotransferases/genetics , Transcription Factors/geneticsABSTRACT
Alveolar rhabdomyosarcoma (ARMS) is an aggressive paediatric cancer of skeletal muscle with poor prognosis. A PAX3-FOXO1 fusion protein acts as a driver of malignancy in ARMS by disrupting tightly coupled but mutually exclusive pathways of proliferation and differentiation. While PAX3-FOXO1 is an attractive therapeutic target, no current treatments are designed to block its oncogenic activity. The present work shows that the histone acetyltransferase P/CAF (KAT2B) is overexpressed in primary tumours from ARMS patients. Interestingly, in fusion-positive ARMS cell lines, P/CAF acetylates and stabilizes PAX3-FOXO1 rather than MyoD, a master regulator of muscle differentiation. Silencing P/CAF, or pharmacological inhibition of its acetyltransferase activity, down-regulates PAX3-FOXO1 levels concomitant with reduced proliferation and tumour burden in xenograft mouse models. Our studies identify a P/CAF-PAX3-FOXO1 signalling node that promotes oncogenesis and may contribute to MyoD dysfunction in ARMS. This work exemplifies the therapeutic potential of targeting chromatin-modifying enzymes to inhibit fusion oncoproteins that are a frequent event in sarcomas. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
