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Chondrosarcoma F1000Research 2018, 7(F1000 Faculty Rev):1826 Last updated: 17 JUL 2019 REVIEW Chondrosarcoma: biology, genetics, and epigenetics [version 1; peer review: 2 approved] Warren A Chow Department of Medical Oncology & Therapeutics Research, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA First published: 20 Nov 2018, 7(F1000 Faculty Rev):1826 ( Open Peer Review v1 https://doi.org/10.12688/f1000research.15953.1) Latest published: 20 Nov 2018, 7(F1000 Faculty Rev):1826 ( https://doi.org/10.12688/f1000research.15953.1) Reviewer Status Abstract Invited Reviewers Chondrosarcomas constitute a heterogeneous group of primary bone 1 2 cancers characterized by hyaline cartilaginous neoplastic tissue. They are the second most common primary bone malignancy. The vast majority of version 1 chondrosarcomas are conventional chondrosarcomas, and most published conventional chondrosarcomas are low- to intermediate-grade tumors 20 Nov 2018 (grade 1 or 2) which have indolent clinical behavior and low metastatic potential. Recurrence augurs a poor prognosis, as conventional chondrosarcomas are both radiation and chemotherapy resistant. Recent F1000 Faculty Reviews are written by members of discoveries in the biology, genetics, and epigenetics of conventional the prestigious F1000 Faculty. They are chondrosarcomas have significantly advanced our understanding of the commissioned and are peer reviewed before pathobiology of these tumors and offer insight into potential therapeutic publication to ensure that the final, published version targets. is comprehensive and accessible. The reviewers Keywords who approved the final version are listed with their chondrosarcoma, genetics, epigenetics biology names and affiliations. 1 Robin L Jones, Sarcoma Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK 2 Shreyaskumar Patel, The University of Texas MD Anderson Cancer Center, Houston, USA Any comments on the article can be found at the end of the article. Page 1 of 9 F1000Research 2018, 7(F1000 Faculty Rev):1826 Last updated: 17 JUL 2019 Corresponding author: Warren A Chow ([email protected]) Author roles: Chow WA: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2018 Chow WA. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Chow WA. Chondrosarcoma: biology, genetics, and epigenetics [version 1; peer review: 2 approved] F1000Research 2018, 7(F1000 Faculty Rev):1826 (https://doi.org/10.12688/f1000research.15953.1) First published: 20 Nov 2018, 7(F1000 Faculty Rev):1826 (https://doi.org/10.12688/f1000research.15953.1) Page 2 of 9 F1000Research 2018, 7(F1000 Faculty Rev):1826 Last updated: 17 JUL 2019 Introduction cells differentiate at the epiphyseal growth plate into resting Chondrosarcoma (CS) is the collective term for a group of chondrocytes, which then migrate into a proliferative zone, heterogeneous, generally slow-growing, primary malignant where they multiply and increase the cellularity of the matrix tumors of bone characterized by the formation of hyaline car- (Figure 1). These proliferative cells then leave the epiphyseal tilaginous neoplastic tissue. They primarily affect adults and plate before undergoing a hypertrophic phase, whereby they are the second most common primary solid tumor of bone after mature into large clear cells. Eventually, the cells undergo osteogenic sarcoma1. CS account for approximately 3 new cases apoptosis, leaving behind the characteristic hypocellular hyaline per 106 population per year2. The prognosis for the majority of cartilage matrix. Osteoblasts then migrate into this matrix and patients with CS is favorable and correlates with histologic grade initiate ossification15. and adequate surgical margins3. Development of pulmonary met- astatic disease is typically an ominous sign, however, owing to (Benign) cartilaginous neoplasms chemotherapy and radiation resistance. This is a result of its under- Osteochondromas are benign cartilaginous neoplasms consist- lying phenotype: poor vascularization, slow division rate, and hya- ing of a cartilage-capped bony projection on the surface of the line cartilaginous matrix prohibiting access to the cells. Recent bone, containing a marrow cavity continuous with the under- research on the biology, genetics, and epigenetics of CS will be lying bone16. They are one of the most common benign bone reviewed. tumors. Approximately 15% of cases present with multiple lesions characteristic of the autosomal dominant multiple osteochon- More than 90% of CS are conventional CS3. Approximately droma (MO) genetic disorder. The risk of malignant transforma- 90% of these are low- to intermediate-grade (grade 1–2) and tion to secondary peripheral CS is estimated at 1% for sporadic behave indolently and rarely metastasize3. Only 5–10% of osteochondroma and less than 5% for MO17. Biallelic inactiva- conventional CS are grade 3 and have high metastatic potential4. tion of the exostosin glycosyltransferase (EXT1 or EXT2) genes CS that arise unassociated with a pre-existing lesion are called is observed in the majority of both sporadic and hereditary primary CS, and they are known as secondary if they develop osteochondroma cases18,19. The EXT proteins are required for from a pre-existing benign cartilage tumor such as an enchon- the polymerization of heparan sulfate (HS) chains forming droma or osteochondroma. They are further classified as central the hyaline cartilage. when they arise within the medullary cavity and peripheral when they arise from the bone surface, generally from the cartilage cap Interestingly, the cells of peripheral CS are predominantly of an exostosis. Primary CS are nearly always central; second- EXT1 positive20, unlike the EXT1-negative cells within osteo- ary CS can be central or peripheral5. Although CS are considered chondromas. Hence, EXT loss is likely an early event. The both chemotherapy and radiation resistant, there are rare case EXT-negative cells in osteochondroma create an extracellular reports of responses to conventional chemotherapeutic agents, mutation-promoting environment, whereupon neighboring EXT- including gemcitabine6,7. positive cells acquire late-stage mutations that cause malignant transformation into CS. Variant CS subtypes are significantly less common1,4,5. Dedif- ferentiated CS develop when low-grade conventional CS trans- Enchondromas are benign cartilaginous neoplasms that arise form into a high-grade sarcoma, most frequently exhibiting within the medullary cavity of bone, in contrast to osteochon- features of osteosarcoma, fibrosarcoma, or undifferentiated pleo- dromas, which arise on the surface. Histologically, they closely morphic sarcoma (UPS). Mesenchymal CS (MCS) is a highly resemble grade 1 CS, and radiographic correlation for benign malignant tumor exhibiting a bimorphic histologic pattern, with features is necessary for diagnosis. Mutations in the isocitrate a highly undifferentiated small round cell component admixed dehydrogenase (IDH) 1 and 2 genes are present in 85% of hered- with islands of well-differentiated cartilage. The HEY1–NCOA2 itary enchondromatosis-associated disorders, Ollier disease fusion has been identified in MCS8. Delayed recurrences after (enchondromatosis only), and Maffuci syndrome (enchondro- more than 20 years are not uncommon9. Clear cell CS is a low- matosis and hemangiomas) and 50% of solitary enchondromas21. grade malignant tumor that most commonly involves the epi- The risk of transformation into secondary central CS in patients physes of the long bones; the tumor cells are clear because their affected by enchondromatosis is approximately 40% for Ollier cytoplasm contains large amounts of glycogen10. Extraskeletal disease and up to 53% in Maffuci syndrome22. myxoid CS is also a slow-growing soft-tissue tumor contain- ing prominent myxoid degeneration and characterized by a IDH mutations are present in 52–59% of central CS and 57% prolonged clinical course despite high rates of local recurrence of dedifferentiated CS23. The presence of IDH mutations in and metastases11. It is characterized by t(9;22)(q22;q12), fus- benign enchondromas and malignant CS supports the notion that ing EWSR1 to NRA3 (genes formerly termed CHN, TEC, or IDH mutations are an early event, and these cartilaginous neo- NOR1)12. Other translocation partners to NRA3 include TAF15 plasms represent a spectrum of malignant potential. IDH muta- and TCF1213,14. Because of the rarity of these variant CS, the tions are found in gliomas, acute myeloid leukemia (AML), remainder of this review will be dedicated to the more-prevalent and cholangiocarcinomas24. IDH is an enzyme involved in the conventional CS subtype. tricarboxylic acid cycle (Krebs cycle), where it normally con- verts isocitrate to α-ketoglutarate (α-KG). Mutant IDH (mIDH) Normal bone formation loses the ability to convert isocitrate to α-KG and gains a new Normal bone formation is a result of the production of hyaline function that leads to the accumulation of δ-2-hydroxyglutarate cartilage matrix produced
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