Article

EXT-Mutation Analysis and Loss of Heterozygosity in Sporadic and Hereditary Osteochondromas and Secondary Chondrosarcomas

Departments of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
The American Journal of Human Genetics (Impact Factor: 10.99). 10/1999; 65(3):689-98. DOI: 10.1086/302532
Source: PubMed

ABSTRACT Osteochondromas occur as sporadic solitary lesions or as multiple lesions, characterizing the hereditary multiple exostoses syndrome (EXT). Approximately 15% of all chondrosarcomas arise within the cartilaginous cap of an osteochondroma. EXT is genetically heterogeneous, and two genes, EXT1 and EXT2, located on 8q24 and 11p11-p12, respectively, have been cloned. It is still unclear whether osteochondroma is a developmental disorder or a true neoplasm. Furthermore, it is unclear whether inactivation of both alleles of an EXT gene, according to the tumor-suppressor model, is required for osteochondroma development, or whether a single EXT germline mutation acts in a dominant negative way. We therefore studied loss of heterozygosity and DNA ploidy in eight sporadic and six hereditary osteochondromas. EXT1- and EXT2-mutation analysis was performed in a total of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas. We demonstrated osteochondroma to be a true neoplasm, since aneuploidy was found in 4 of 10 osteochondromas. Furthermore, LOH was almost exclusively found at the EXT1 locus in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations were detected in exon 1 of EXT1. Two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild-type allele in three osteochondromas, indicating that, in cartilaginous cells of the growth plate, inactivation of both copies of the EXT1 gene is required for osteochondroma formation in hereditary cases. In contrast, no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutations were found in the EXT2 gene.

Full-text

Available from: Egbert Bakker, May 28, 2015
0 Followers
 · 
79 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Knudson's carcinogenic model, which simulates incidence rates for retinoblastoma, provides compelling evidence for a two-stage mutational process. However, for more complex cancers, existing multistage models are less convincing. To fill this gap, I hypothesize that neoplasms preferentially arise when stem cell exhaustion creates a short supply of progenitor cells at ages of high proliferative demand. To test this hypothesis, published datasets were employed to model the age distribution of osteochondroma, a benign lesion, and osteosarcoma, a malignant one. The supply of chondrogenic stem-like cells in femur growth plates of children and adolescents was evaluated and compared with the progenitor cell demand of longitudinal bone growth. Similarly, the supply of osteoprogenitor cells from birth to old age was compared with the demands of bone formation. Results show that progenitor cell demand-to-supply ratios are a good risk indicator, exhibiting similar trends to the unimodal and bimodal age distributions of osteochondroma and osteosarcoma, respectively. The hypothesis also helps explain Peto's paradox and the finding that taller individuals are more prone to cancers and have shorter lifespans. The hypothesis was tested, in the manner of Knudson, by its ability to convincingly explain and demonstrate, for the first time, a bone tumour's bimodal age-incidence curve.
    Mechanisms of Ageing and Development 07/2014; 139. DOI:10.1016/j.mad.2014.06.001 · 3.51 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chondrosarcomas are malignant tumors of chondrocytes and represent the second most common type of primary bone tumors. Within the context of normal chondrogenesis, this review summarizes results from recent research outlining the key molecular changes that occur during the development of this sarcoma type. Current data support the notion that a two-hit scenario, common to many tumors, also underlies chondrosarcoma formation. First, early-stage mutations alter the normal proliferation and differentiation of chondrocytes, thereby predisposing them to malignant transformation. These early-stage mutations, found in both benign cartilaginous lesions and chondrosarcomas, include alterations affecting the IHH/PTHrP and IDH1/IDH2 pathways. As they are not observed in malignant cells, mutations in the EXT1 and EXT2 genes are considered early-stage events providing an environment that alters IHH/PTHrP signaling, thereby inducing mutations in adjacent cells. Due to normal cell cycle control that remains active, a low rate of malignant transformation is seen in benign cartilaginous lesions with early-stage mutations. In contrast, late-stage mutations, seen in most malignant chondrosarcomas, appear to induce malignant transformation as they are not found in benign cartilaginous lesions. These late-stage mutations primarily involve cell cycle pathway regulators including p53 and pRB, two genes that are also known to be implicated in numerous other human tumor types. Now the key genetic alterations involved in both early and late stages of chondrosarcoma development have been identified, focus should be shifted to the identification of druggable molecular targets for the design of novel chondrosarcoma-specific therapies.
    01/2014; 37(2). DOI:10.1007/s13402-014-0166-8
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alongside histomorphology and immunohistochemistry, molecular pathology is now established as one of the cornerstones in the tissue diagnosis of bone tumours. We describe the principal molecular pathological techniques employed, and each of the bone tumour entities where their identified characteristic molecular pathological changes can be detected to support and confirm the suspected histological diagnosis. Tumours discussed include fibrous dysplasia, classical and subtype osteosarcomas, central and surface cartilaginous tumours, Ewing's sarcoma, vascular tumours, aneurysmal bone cyst, chordoma, myoepithelioma, and angiomatoid fibrous histiocytoma. This is a rapidly evolving field with discoveries occurring every few months, and some of the newer entities (the Ewing's-like sarcomas), which are principally identified by their molecular pathology characteristics, are discussed.
    Histopathology 09/2013; DOI:10.1111/his.12275 · 3.30 Impact Factor