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Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.

ABSTRACT: Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.

SUBMITTER: Behjati S

PROVIDER: S-EPMC5490007 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.

Behjati Sam S Tarpey Patrick S PS Haase Kerstin K Ye Hongtao H Young Matthew D MD Alexandrov Ludmil B LB Farndon Sarah J SJ Collord Grace G Wedge David C DC Martincorena Inigo I Cooke Susanna L SL Davies Helen H Mifsud William W Lidgren Mathias M Martin Sancha S Latimer Calli C Maddison Mark M Butler Adam P AP Teague Jon W JW Pillay Nischalan N Shlien Adam A McDermott Ultan U Futreal P Andrew PA Baumhoer Daniel D Zaikova Olga O Bjerkehagen Bodil B Myklebost Ola O Amary M Fernanda MF Tirabosco Roberto R Van Loo Peter P Stratton Michael R MR Flanagan Adrienne M AM Campbell Peter J PJ

Nature communications 20170623

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 ...[more]

PMID: 28643781

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Project description:Mechanical stimulation is necessary for regulating correct formation of the skeleton. Here we test the hypothesis that mechanical stimulation of the embryonic skeletal system impacts expression levels of genes implicated in developmentally important signalling pathways in a genome wide approach. We use a mutant mouse model with altered mechanical stimulation due to the absence of limb skeletal muscle (Splotch-delayed) where muscle-less embryos show specific defects in skeletal elements including delayed ossification, changes in the size and shape of cartilage rudiments and joint fusion. We used Microarray and RNA sequencing analysis tools to identify differentially expressed genes between muscle-less and control embryonic (TS23) humerus tissue.We found that 680 independent genes were down-regulated and 452 genes up-regulated in humeri from muscle-less Spd embryos compared to littermate controls (at least 2-fold; corrected p-value ?0.05). We analysed the resulting differentially expressed gene sets using Gene Ontology annotations to identify significant enrichment of genes associated with particular biological processes, showing that removal of mechanical stimuli from muscle contractions affected genes associated with development and differentiation, cytoskeletal architecture and cell signalling. Among cell signalling pathways, the most strongly disturbed was Wnt signalling, with 34 genes including 19 pathway target genes affected. Spatial gene expression analysis showed that both a Wnt ligand encoding gene (Wnt4) and a pathway antagonist (Sfrp2) are up-regulated specifically in the developing joint line, while the expression of a Wnt target gene, Cd44, is no longer detectable in muscle-less embryos. The identification of 84 genes associated with the cytoskeleton that are down-regulated in the absence of muscle indicates a number of candidate genes that are both mechanoresponsive and potentially involved in mechanotransduction, converting a mechanical stimulus into a transcriptional response.This work identifies key developmental regulatory genes impacted by altered mechanical stimulation, sheds light on the molecular mechanisms that interpret mechanical stimulation during skeletal development and provides valuable resources for further investigation of the mechanistic basis of mechanoregulation. In particular it highlights the Wnt signalling pathway as a potential point of integration of mechanical and molecular signalling and cytoskeletal components as mediators of the response.

Dataset Information

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.

Publications

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.

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