| Summary: | Osteosarcoma is the most common bone malignancy in children and adolescents with
poorly understood aetiology. Recently, disease susceptibility and aetiology in several cancers
have been associated with genomic copy-number (CN) change. We therefore studied the contribution
of CN change in osteosarcoma.
We report that individuals with osteosarcoma have increased germline structural variation
compared to controls. These CN variants (CNVs) preferentially localize to genes implicated
in control of osteoblast differentiation, bone mineralization and ossification. We propose that
germline CNVs contribute to osteosarcoma susceptibility through deregulation of developmental
processes controlled by genes contained within CNVs. Further supporting the notion that
germline CNVs in individuals with osteosarcoma are pathogenic, we demonstrate that CNVs are
associated with poor patient survival. Finally, we characterize two germline CNVs, at chromosome
1q43 and 2p11.2, which are overrepresented in osteosarcoma patients and propose that
they contribute to osteosarcoma susceptibility through effect on neighbouring genes, which
could be involved in control of microtubule dynamics and tumour suppression.
We further characterize two regions in the tumour genome of osteosarcoma patients that
harbour recurrent CN alterations (CNAs). These include deletions at chromosome 3q13.31 and
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amplifications at chromosome 7p14.1, which are the most altered regions in osteosarcoma and
contest the view that CNAs in osteosarcoma are non-recurrent. Both chromosome 3q13.31 and
7p14.1 CNAs involve genes implicated in carcinogenesis, including LASMP at 3q13.31 and
TARP at 7p14.1, while 3q13.31 CNAs also involve two non-coding RNAs. We further show
that expression of 3q13.31 genes correlates with the presence of 3q13.31 CNAs. We report that
chromosome 3q13.31 and 7p14.1 CNAs are also common in other cancers, identifying these loci
as candidates with a global role in carcinogenesis. Supporting the notion that 3q13.31 deletions
play a role in osteosarcomagenesis, we find that depletion of 3q13.31 genes promotes proliferation
of osteoblasts by regulation of apoptotic and cell-cycle transcripts and also VEGF receptor
1 and that genetic deletions of 3q13.31 are associated with poor survival of osteosarcoma patients.
In summary, our study implicates germline and somatic CN changes in osteosarcoma and
represents a model approach for elucidation of elements contributing to disease susceptibility
and aetiology in human cancer.
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