Molecular pathology of osteosarcoma

Acknowledgments

This work has been supported in part by funds provided by the Haley's Hope Memorial Support Fund for Osteosarcoma Research at the University of Alabama at Birmingham.

Introduction

Although osteosarcoma is a relatively rare neoplasm, it is the most common primary bone malignancy, especially with a high incidence rate in childhood and adolescents [ ]. The diagnosis of osteosarcoma largely relies on the correlation of biopsy findings with imaging studies [ ]. While molecular findings continue to be of limited value in the diagnosis of osteosarcoma compared to soft tissue tumors, there have been significant advances in molecular and genetic studies in oncology over the past two to three decades, and osteosarcoma is not an exception. These findings contribute to our understanding of tumor prognosis and yield important information for therapy. Osteosarcoma is an extremely genetically unstable tumor with multiple numerical and structural chromosomal alterations. Genome-wide studies have provided insights to understanding genetic alterations in osteosarcoma. Combining these with the study of syndromes associated with an increased risk of osteosarcoma and research involving animal models, our understanding of these processes has been significantly enhanced. In this chapter, we will review specific tumor suppressor genes, oncogenes, and molecular pathways which have been implicated in the development, progression, and future targeted therapy of osteosarcoma.

Genomic instability and genetic changes

Chromosomal alterations

Conventional osteosarcoma is characterized by highly complex aneuploid karyotypes with multiple numerical and structural chromosomal aberrations. Genomic profiling of tumor DNA using comparative genomic hybridization (CGH), single-nucleotide polymorphism (SNP) arrays, and whole-genome sequencing (WGS) revealed, however, some recurrent chromosomal alterations. Recurrent amplifications and copy number gains have been detected in 1q10-q12, 1q21-22, 1q21-q31, 1p36, 4q12, 5p13, 6p21, 6p22, 7p13, 7p22, 7q31, 8q11, 8q24, 9p24, 12q13, 12q14, 12q15, 14q32, 17p11, 17p12, 19q12, 19q13, and 21q, whereas deletion or loss of heterozygosity (LOH) is reported in 3q13, 6q, 7p21, 7q31, 8p21, 9p13, 9p21, 10q23, 10q26, chr 11, 15, 16p, 13q14, 16q23, 17p13, 17q11, 19q, and Xq21 [ ].

LOH at 3q13 includes the LSAMP gene, which has been reported as a tumor suppressor gene, appearing to correlate with disease progression and poor survival [ ]. Amplification of the chromosomal region 6p12-21 has been observed frequently at a rate of between 16% and 75%. A candidate gene in this amplified region is the RUNX2 gene, which is a transcription factor required for osteoblast differentiation [ ]. Elevated RUNX2 levels have been reported in conventional osteosarcoma and high levels of RUNX2 expression is associated with increased disease recurrence and/or metastasis. RUNX2 is also thought to have a synergistic effect on cell cycle progression in the presence of TP53 and RB1 alteration, both of which are commonly seen in high-grade osteosarcomas [ ]. Another region that is widely reported to be amplified is 8q24.2 [ ]. This region includes the MYC oncogene and its amplification is seen in 7%–67% of osteosarcoma [ , ]. Elevated MYC expression is associated with poor prognosis and might promote the metastasis of osteosarcoma [ ].

Chromothripsis

A possible proposed mechanism for this instability is known as “Chromothripsis” (from the Greek, “thripsis” = “shattering”) [ ] ( Fig. 40.1 ). Chromothripsis is thought to be induced by a single catastrophic event resulting in massive genomic rearrangements and localized hypermutation, promoting incremental development and progression of cancer [ ]. Additionally, chromothriptic breakpoints are sometimes accompanied by “Kataegis” (from the Greek, “kataegis” = “shower” or “thunderstorm”). Kataegis is a phenomenon due to regional hypermutation characterized by multiple base mutations occurring at nearby rearrangement breakpoints. They have been detected in approximately 50%–85% osteosarcoma samples [ , ]. The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) protein families are believed to be involved in this process [ ]. Chromothripsis has been observed in up to 33% of osteosarcoma patients [ , ] and is also associated with poor patient survival, indicating its potential relevance as a prognostic marker [ ]. Although there is evidence of these cataclysmic events in genomes, the mechanisms that give rise to them are still not well characterized. Future study may reveal the functional consequences and mechanistic basis of chromothripsis.

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