Genetic aspects of primary bone tumors

Research highlights

Recurrent genomic rearrangements and specific somatic mutations in bone tumors are leading to new diagnostic tests.
Deregulated fusion transcription factors are revealing how epigenomic changes may underlie Ewing's sarcoma oncogenesis.
Deep sequencing studies have contributed toward improved understanding of the complex genomics of osteosarcoma.
Specific genetic alterations are identifying driver pathways in bone tumors that are new therapeutic opportunities.

Introduction

Primary neoplasms of the skeleton are relatively rare, comprising only 0.2% of human tumors. Despite this low frequency, this group of lesions poses a significant challenge in clinical management, with 3600 new cases predicted and 1720 deaths estimated to occur in the United States in 2020. This clinical challenge is due in part to the heterogeneity of this group, as the lesions vary widely in their morphology, making histopathological diagnosis difficult. Moreover, there is wide diversity in the biological behavior, ranging from innocuous to rapidly progressive, including many of intermediate malignancy, behaving as locally aggressive but nonmetastatic tumors. In the face of this diversity, accurate diagnoses and staging is critical in the treatment strategy, and ultimately in determining the morbidity and mortality.

With advancements in genomics and cancer genetics, the critical events associated with the development of several bone cancers are now being unraveled. Identification of recurrent changes has resulted in the definition of an ever-increasing number of tumor-related molecular alterations and is fostering a continual refinement of the molecular pathology of these tumors [ ]. The majority of bone tumors are classified according to the tissue of origin. The growing catalog of new molecular information promises to provide useful tools as an adjunct to histological diagnosis and prognostication in a field in which, due to both the variety of tumor phenotypes and their relative paucity, pathological diagnosis and clinical management are often difficult. In addition, our evolving insight of the biological mechanisms and signaling pathways underlying the tumor progression offers possibilities of novel, targeted therapeutic options in the future. The new WHO online classification system [ ] includes diagnostic criteria, pathological features, and associated molecular alterations presented in a disease-oriented manner.

Overall, matrix-producing and fibrous tumors are the most commonly seen neoplasm. Of the benign tumors, osteochondroma and fibrous cortical defects have the highest incidences, while osteosarcoma (OS), chondrosarcoma, and Ewing's sarcoma (ES) are the most frequent primary bone malignancy excluding those of marrow origin (myeloma, lymphoma, and leukemia). This chapter aims to provide a brief overview of the genetics of some of the more common bone tumors, both benign and malignant. It will focus on the well-known genetic and cytogenetic lesions that have led to the molecular diagnostics of these tumors. This chapter is by no means an exhaustive survey of the genetics of all bone malignancies, and the readers are referred to other resources for a more comprehensive listing [ ].

Cartilaginous neoplasms

The classification of chondroid neoplasms is complex. As with all bone tumors, objective assessment of the usefulness of genetic analysis requires careful comparison with tumor diagnosis, which in turn is critically dependent on the integration of histological and radiographic findings with clinical information.

Benign

Benign tumors of cartilages are the most common primary bone tumors that arise in the pediatric population.

Osteochondroma

Osteochondroma is the most common benign neoplasm of the bone. It is defined as a benign outgrowth from the cortical bone surface of medullary and cortical bone with a cartilaginous cap. Generally, osteochondromas occur in bones formed by enchondral ossification [ ]. While the majority of osteochondromas arise spontaneously, there is a familial form recognized as hereditary multiple exostoses syndrome (HME), an autosomal dominant skeletal disorder associated with excessive bony growths [ ]. In 10% of osteochondroma associated with HME, malignant transformation occurs within the cartilaginous cap, leading to a secondary peripheral chondrosarcoma. Conversely, about 15% of all chondrosarcomas arise secondarily to osteochondroma [ ]. The molecular mechanisms of HME and solitary osteochondromas have been extensively studied since the two genes encoding exostosin glycosyltransferase EXT1 and EXT2 , located at 8q24 and 11p11-p12, respectively, were identified to cause multiple osteochondromas [ ]. Patients with multiple osteochondromas have heterozygous germline alterations of the EXT1 or EXT2 gene. Loss of the wild-type allele in HME cases and homozygous loss of both alleles in sporadic cases indicates that inactivation of both EXT alleles of this tumor suppressor gene are required for osteochondroma formation [ ]. Inactivation of Ext1 in chondrocytes in mouse models also confirms that this gene functions as a tumor suppressor gene cartilage-forming cells [ ]. Additional support comes from the fact that in solitary osteochondroma, homozygous deletion of EXT1 gene is only occurring in the chondrocytes of the cartilaginous cap [ ].

At the molecular level, the majority of mutations that have been identified in EXT1 and EXT2 are nonsense, frameshift, or splice-site [ ], which have been reported to cause truncation, premature termination, or premature degradation of EXT proteins in over 70% of HME cases [ ]. There is also increasing interest in the causative role of miRNA in cartilage diseases and chondrogenesis [ ]. It has been shown that differentially expressed miRNAs in multiple osteochondromas may regulate genes responsible for normal proliferation and differentiation of chondrocytes and could also contribute to pathogenesis and clinical outcome [ ].

The various regulatory networks that may play a role in osteochondroma signaling have been recently reviewed [ ]. EXT1 and EXT2 are transmembrane glycosyltransferases involved in the synthesis of heparin sulfate, a key molecule in adjusting chondrocyte proliferation and bone growth [ ]. Both proteins are localized to the endoplasmic reticulum in a hetero-oligomeric complex that has much greater glycosyltransferase activity than either protein alone [ ]. Inactivation of EXT results in altered heparin sulfate expression at the cell surface of chondrocytes and adversely affects Hedgehog (Hh), parathyroid hormone–related peptide and fibroblast growth factor (FGF) signaling pathways [ ], and loss of polarization of chondrocytes [ ]. Recent studies based on genetic fate mapping have shown that the commitment of growth plate chondrocytes into the skeletal lineage occurs under the influence Hh signals during endochondral bone formation [ ]. EXT1 or EXT2 deleted cells do not synthesize suficient amounts of the heparin sulfate-rich proteoglycan substrate, which is vital for regulating the binding and difiusion of Hh ligands on the cell surface [ ].

Chondroma

Chondromas are common neoplasms, and can occur in the bone (enchondroma), the periosteum (periosteal chondroma), and in soft tissues (soft-part chondroma), typically affecting the proximal phalanges of the hands and feet. No distinctive cytogenetic or molecular findings distinguish among the various types of chondroma. The genetics of chondromas are not extensively defined. However, the data from a few comparative genomic hybridization (CGH) studies indicate an uncomplicated profile, including gains of 13q21 and losses on chromosomes 19 and 22q [ ]. Rearrangements of chromosome 6 seem to be recurrent in chondromas, including an isochromosome of the short arm of chromosome 6(p10), as well as t(12;15)(q13;q26) [ ]. The nonrandom translocation of the 12q13-15 segment has been shown to involve the HMGA2 (HMGI-C) locus as the critical site [ , ].

Soft tissue chondromas were recently shown to harbor recurrent FN1–FGFR1 and FN1–FGFR2 gene fusions [ ]. All the soft tissue chondromas harboring FN1 alterations exhibited “grungy calciﬁcation,” a ﬁnding that in some cases has similarities to chondroblastomas, and led to the original description of the chondroblastoma-like variant [ ].

Approximately 30% of the chondromas present as multiple lesions [ ]. These cases are typically syndromic in nature, overlapping with spindle cell hemangioendotheliomas in Maffucci's syndrome, or with ovarian sex-cord stromal tumors in Ollier's disease [ , ]. Ollier's disease is a rare, nonhereditary disorder characterized by multiple enchondromas in children and adults. These patients have a significantly higher risk of malignant transformation into chondrosarcoma [ ]. Maffucci's syndrome is similar to Ollier's disease, but these patients have a lower rate of malignant transformation [ ]. A significant proportion of patients with Ollier's disease and Maffucci's syndrome were shown to carry mutations in their tumors, with most of the alterations affecting the Arg132 position in exon 4 of IDH1 [ ] . Mutations in IDH2 are rare. Both IDH1 and IDH2 catalyze oxidative steps in the Krebs tricarboxylic acid cycle. Mutations in the IDH1 and IDH2 genes are also found in primary and secondary central chondrosarcomas as well as in central and periosteal chondrosarcomas [ , ] (discussed below). The genetics of the functional alterations associated with the metabolic enzymes involved in mesenchymal tumor predisposition syndromes was recently reviewed [ ].

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