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

Sam Behjati,Matthew D Young,Ultan Mcdermott,Kerstin Haase,Sancha Martin,Olga Zaikova,Peter Van Loo,Maria Fernanda Amary ,Mark Maddison,Ludmil B Alexandrov,Grace Collord,Nischalan Pillay,Adam Shlien,Patrick Tarpey ,Helen Davies,Hongtao Ye,Adrienne M Flanagan,Iñigo Martincorena ,William Mifsud,Susanna L Cooke,Jon W Teague,Roberto Tirabosco,Adam Butler ,Calli Latimer,Daniel Baumhoer,Sarah J Farndon,David C Wedge,Michael R Stratton,P Andrew Futreal,Mathias Lidgren,Ola Myklebost,Bodil Bjerkehagen,Peter J Campbell

doi:10.1038/ncomms15936

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.

Highlights

Osteosarcoma is a primary malignancy of bone that affects children and adults
We describe a distinct pattern of genomic rearrangement, chromothripsis amplification, that generates driver mutations across the osteosarcoma genome
Using fluorescence in situ hybridization (FISH), which allows sensitive and specific examination of individual tumour cells, we found high-level amplification of IGF1 receptor (IGF1R), defined as 15 copies or more, in 12/87 (14%) cases (Supplementary Data 6 and Supplementary Fig. 2)

Summary

Introduction

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. 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. In a whole genome study of osteosarcoma, structural variants were identified as a major source of driver mutation. Some of these variants occurred in the context of chromothripsis, the shattering of chromosomes resulting in copy number oscillations[3]. We describe a distinct pattern of genomic rearrangement, chromothripsis amplification, that generates driver mutations across the osteosarcoma genome

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