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

Nat Commun. 2017 Jun 23;8:15936. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • Female
  • Gene Rearrangement*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Middle Aged
  • Mutation*
  • Osteosarcoma / genetics*
  • Osteosarcoma / metabolism
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Signal Transduction
  • Young Adult

Substances

  • IGF1 protein, human
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1