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Sarcomas With Complex Genetic Changes

Gill, Jonathan MD; Gorlick, Richard MD

doi: 10.1097/01.COT.0000499602.59834.e5


Sarcomas comprise a heterogeneous group of tumors consisting of greater than 30 subtypes. The subtypes can be grouped by their histologic appearance or in more recent nomenclature the believed cell of origin: adipocytic, cartilage, Ewing sarcoma/primitive neuroectodermal, fibroblastic, fibrohistiocytic, gastrointestinal stromal, giant cell, nerve sheath, osteogenic, skeletal muscle, smooth muscle, pericytic/perivascular, vascular, and undifferentiated sarcomas.

Within these subtypes, there are varying degrees of malignant potential with low-grade tumors having low metastatic potential (<10%) and high-grade tumors having a high-risk of metastasis (>50% of patients).

Sarcomas can be divided in terms of their genetic alterations into two groups: characterized by the presence of a chromosomal translocation (Table). The translocations in these sarcomas are disease defining and the rest of the genome is relatively normal. The second and larger group of sarcomas are those with complex genetic changes.

Even within one histiotype examples of both genetic bases may exist. For example, rhabdomyosarcoma can be divided by histology into embryonal and alveolar subtypes. Alveolar rhabdomyosarcoma is defined most commonly by the PAX-FKHR t(2;13) translocation, whereas embryonal rhabdomyosarcoma is a genetically complex sarcoma.

In embryonal rhabdomyosarcomas, which as a group do not have the characteristic translocation, the rate of somatic nonsynonymous mutations is nearly three times the level of translocation-positive alveolar rhabdomyosarcomas. Interestingly, the number of somatic single nucleotide variants in these patients increase linearly with age. This is suggestive that, for the youngest patients with the least mutations, sufficient time had not lapsed to acquire further bystander mutations, or that the pathogenic disease causing mutations had occurred early, leading them to develop the disease at a younger age.

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Osteosarcoma represents one of the sarcoma with the greatest genetic heterogeneity. Most osteosarcomas harbor aberrations in TP53. Alterations in TP53 include mutations, deletions, and translocations leading to breakpoints in 80-95 percent of tumors examined.

In those not harboring mutations in TP53, most tumors have amplification of MDM2, a known repressor of p53. In addition, 20-33 percent of osteosarcomas harbor alterations in RB1 (Oncotarget 2016;7:5273-88). As such, osteosarcomas have tremendous genomic instability. Circos plots demonstrate genome wide chromosomal translocations, with complete disarray of the normal karyotype.

Osteosarcoma was one of the cancers described as an example in the initial description of chromothripsis, chromosome shattering. Though, others have argued that the process more closely resembles kataegis, a pattern of localized hypermutation leading to chromosomal fragility and translocations. Ostesoarcomas harbor approximately 1.2 mutations per megabase, placing it in the middle of the pack of somatic mutations in human cancer. The genomic instability in osteosarcoma leads to significant intertumor as well as intratumor genomic heterogeneity.

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Chondrosarcomas serve as another model of acquired genetic instability leading to malignant transformation. Chondrosarcomas are rare malignant cartilage forming bone tumors. In rare cases, chondrosarcomas can arise from benign tumors and can be divided into two groups: central chondrosarcomas and secondary peripheral chondrosarcomas.



Central chondrosarcomas, localized to the medullary cavity of long bones, make up the majority of cases and may rarely derive from enchondromas. Since most enchondromas are benign asymptomatic lesions, the rate of malignant transformation is uncertain but estimated to approach 4 percent. However, in patients with syndromes leading to multiple enchondromas, Ollier and Maffucci, chondrosarcomas occur in 40 percent of patients, which may have a variable latency between 6 months to 30 years.

This suggests a potential mechanism of a stepwise process of malignant transformation in which an initiating mutation leads to altered growth of the multiple benign lesions, but which requires further mutations for malignant transformations. Mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) have been described in both enchondromas and chondrosaromas, and the introduction of a mutant IDH gene in a conditional transgenic mouse was sufficient to cause multiple enchondromas, which may then be an initiating event in the process of malignant transformation (Proc Natl Acad Sci USA 2015;112:2829-34). There are currently three clinical trials of IDH inhibitors in chondrosarcomas as well as other malignancies that harbor mutations in IDH.

Secondary peripheral chondrosarcomas comprise a minority of cases and derive from pre-exisiting osteochondromas. Similarily, peripheral chondrosarcomas occur rarely in less than 1 percent of patients with sporadic osteochondromas, but have been described in about 1-5 percent of patients with hereditary multiple exostoses, known to harbor germline mutations in EXT1 and EXT2, and glycotransferases that elongate heparan and may have tumor suppressor activity.

A comparable mechanism of stepwise malignant transformation can be inferred in the development of malignant peripheral nerve sheath tumors (MPNST) in neurofibromatosis. However, even in this population, malignant transformation is a rare event: estimated that MPNSTs occur in approximately 10 percent of patients of with neurofibromatosis, type 1.

In MPNST, as in chondrosarcomas, the majority of the patients who develop the malignancy do not have an underlying predisposition (genetic or precursor benign lesions). From this we can conclude, that although an underlying genetic alteration may be an initiating event, it is neither required nor sufficient for malignant transformation. For example, patients with MPNST and NF-1 are more likely to have activation of EGFR, Raf, and PI3K/AKT pathways, whereas those with sporadic MPNSTs are more likely to carry mutations in TP53 (Am J Surg Pathol 2016;40:896-908).

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Personalized Sarcoma Treatment

The genetic complexity in sarcomas is then not only defined by the mutational load of the individual tumor, but also by the fact that different patients with the “same disease” may have different underlying biochemical alterations leading to malignant transformation.

The histologic grouping of sarcomas by their presumed cell of origin belies a common pathophysiology. The histologic classification of genetically complex sarcomas is thus primarily descriptive of the tissue milieu in which the malignant transformation occurred.

Unlike sarcomas associated with translocations, genetically complex translocations present a significant challenge in defining a driver mutation leading to the malignant transformation. This is further confounded by the fact that each histology is rare, requiring they are often grouped together in clinical trials to test a common treatment protocol. The results usually demonstrate variable response between and within histologies.

As we improve our understanding of the different potential driver mutations and improve our ability to detect actionable targets, these entities may derive benefit of personalized approaches in treating our patients. Given the rarity of these tumors and the heterogeneity within the histologic subtypes, designing clinical trials testing these approaches presents additional challenges.

Likewise, while immunotherapy with checkpoint inhibitors presents a potential option for some patients, there is a need to describe biomarkers for those patients most likely to benefit as our current definition of histologic subtypes may not provide sufficient precision.

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Learning Objective for This Month's CME Activity: After participating in this CME activity, readers should be better able to discern the varying degrees of malignant potential within the histologic subtypes of sarcomas.

JONATHAN GILL, MD, is an Attending Physician, Division of Pediatric Hematology/Oncology and Blood & Marrow Cell Transplantation, Children's Hospital at Montefiore, and Assistant Professor, Albert Einstein College of Medicine, Bronx, N.Y. RICHARD GORLICK, MD, is the Vice Chairman, Department of Pediatrics; Division Chief, Pediatric Hematology/Oncology; and Attending Physician, The Children's Hospital at Montefiore, and Professor of Pediatrics and Molecular Pharmacology, Albert Einstein College of Medicine.

Jonathan Gill, MD

Jonathan Gill, MD

Richard Gorlick, MD

Richard Gorlick, MD

Wolters Kluwer Health, Inc. All rights reserved.
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