Molecular biology of sarcoma

Abstract

Soft tissue sarcomas are a large group of heterogenous neoplasms, many of them are highly aggressive. Most of the cases are sporadic, without any well-defined pathogenetic factor. Potential risk factors are ionizing radiation, lymphatic oedema (secondary angiosarcoma of the breast), viral infections (HHV8 and Kaposi sarcoma), exposure to chemical factors (vinyl chloride and hepatic angiosarcoma). Genetic susceptibility plays a role in a minority of cases. However, mutations in TP53, ATM and ATR genes are associated with enhanced susceptibility to radiation. Li-Fraumeni syndrome (autosomal dominant TP53 mutation) predisposes to development of malignancies, one third of them are sarcomas. Genetic alterations observed in sarcomas could be divided into three major groups characterized by: (1) chromosome translocations; (2) simple karyotype and mutations; (3) variably complex karyotypes. A large part of sarcomas belong to the first group and the specific chromosal translocations could be utilized in the diagnostic process. A smaller number of sarcomas could be assigned to the second group, e.g. desmoid fibromatosis (CTNNB1 or APC mutations) and GIST (KIT, PDGFRA, or less frequently BRAF, SDH, NF1). A large number of sarcomas are characterized by complex and variable karyotypes. Gene copy number alterations are frequent in this group, e.g. in well-differentiated liposarcoma there is an amplification of MDM2, CDK4 and HMGA2 genes or sarcoma-specific chromosomal break regions present in the CHOP gene in myxoid liposarcoma and FKHR in alveolar rhabdomyosarcoma.

Chondrosarcoma-from Molecular Pathology to Novel Therapies

“…However, Friend leukemia virus integration 1 (FLI-1), smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), keratins, and integrase interactor 1 (INI1) are entirely negative for mesenchymal CHS [ 31 ]. Dedifferentiated CHS develops when a part of conventional low-grade CHS transits into aggressive, high-grade sarcoma (most commonly undifferentiated pleomorphic sarcoma, osteosarcoma, or other less frequent high-grade sarcomas, like angiosarcoma, leiomyosarcoma, and rhabdomyosarcoma) [ 32 ]. The non-cartilaginous component might be of different size and may correlate with the tumor malignancy [ 27 , 33 ].…”

“…In differentiation among sarcomas, gene fusions play a huge role; nevertheless, they are not well-known in CHS. One of the most common gene fusion recognized in mesenchymal CHS is between hairy/enhancer-of-split related with YRPW motif 1 ( HEY1 ) and nuclear receptor coactivator 2 ( NCOA2 ) genes, which is a deletion or translocation in the 8 chromosome region (q13;q21), involved in the transition of epithelial cells into its mesenchymal form [ 32 , 92 , 93 ]. Another recently discovered gene fusion in mesenchymal CHS is a translocation between chromosomes 1 and 5—t(1;5)(q42;q32)—concerning interferon regulatory factor 2-binding protein 2 ( IRFBP2 ) and caudal type homeobox 1 ( CDX1 ) genes [ 94 ].…”

Biological Heterogeneity of Chondrosarcoma: From (Epi) Genetics through Stemness and Deregulated Signaling to Immunophenotype

“…Gene copy alterations are frequent events in ChS, as is generally the case in sarcomas [ 66 ]. In a study by Hallor et al, 59/67 of conventional (both peripheral and central) ChS displayed abnormal DNA copy number in almost one-third of the genome with a median total size of the imbalance of 826 Mb [ 67 ].…”

“…A well-known mechanism underlying DNA and histone methylation alterations is an accumulation of 2HG (2-hydroxyglutarate) induced by mutations in IDH1 / 2 in cancer cells, as mentioned above [ 91 ]. For example, the IDH2 mutation has been shown to induce the 2HG-dependent DNA hypermethylation in ChS cells, inhibiting mesenchymal differentiation [ 66 ]. Treatment with a 5-azacytidine can potentially reverse this blockage of the differentiation.…”

Molecular Biology of Osteosarcoma

“…Disruptions in signaling pathways of TP53, Rb, RecQ Like helicase 4, Bloom Syndrome RecQ Like helicase and Werner Syndrome RecQ helicase are risk factors in the pathogenesis of OS. Therefore children and adolescents suffering from genetic syndromes such as Li-Fraumeni, hereditary retinoblastoma, Rothmund-Thomson, Bloom or Werner syndrome are more prone to developing OS [4,6]. The second peak of osteosarcoma in older patients is related to higher risk of Paget's disease of bone (PDB) and increased bone resorption by osteoclasts.…”