Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency

Abstract

Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpreted in the context of mutation and SNP array data from a replication set of 92 tumours. We identify 14 genes as the main drivers, of which some were formerly unknown in the context of osteosarcoma. None of the drivers is clearly responsible for the majority of tumours and even TP53 mutations are frequently mapped into subclones. However, >80% of osteosarcomas exhibit a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours. Our findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited.

Cancer stem cells in osteosarcoma

“…Deeper insight into this diversity therefore holds great promise to identify markers associated with the most aggressive tumour cells within a tumour mass. The vast heterogeneity found in osteosarcoma is shown in an exome sequencing study in which multiple pathways (14 driver genes) were identified (1). The authors suggest that no single driver gene can be pinpointed to be the cause of the majority of investigated tumours and that several oncogenic pathways cause genetic instability in osteosarcoma development.…”

Drugs in early clinical development for the treatment of osteosarcoma

“…Similarly, Kovacs studied the genetic alterations of 31 osteosarcomas and demonstrated that more than 80% of the cases could be explained by the fact that they exhibited a specific combination of single+base substitutions, a loss of heterozygosity, or large+scale genome instability. They identified alterations in 14 driver genes ( , [14]. They also proposed a new model for osteosarcoma development in which a and/or mutant cell initiated a monoclonal disease.…”

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…Based on genome sequencing analyses, a model of the natural history of osteosarcoma has been proposed recently [9]. These authors theorized that the disease may be initiated by a mutation of TP53 and/or Rb1 which show a very high recurrence in osteosarcoma.…”

“…Indeed, osteosarcoma is one of the most heterogeneous cancer types from a genetic point of view with, for instance, in a series of 44 samples more than 80 point mutations and 4 deletions related to 82 different genes [10]. Despite this heterogeneity, more than 80% of osteosarcomas evidence a signature characteristic of Breast Cancer (BRCA) genes 1/2-deficient tumors that open new therapeutic options by using PARP inhibitors [9].…”