Molecular Pathogenesis and Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

Abstract

Sarcomas are infrequent mesenchymal neoplasms characterized by notable morphological and molecular heterogeneity. Molecular studies in sarcoma provide refinements to morphologic classification, and contribute diagnostic information (frequently), prognostic stratification (rarely) and predict therapeutic response (occasionally). Herein, we summarize the major molecular mechanisms underlying sarcoma pathogenesis and present clinically useful diagnostic, prognostic and predictive molecular markers for sarcoma. Five major molecular alterations are discussed, illustrated with representative sarcoma types, including 1. the presence of chimeric transcription factors, in vascular tumors; 2. abnormal kinase signaling, in gastrointestinal stromal tumor; 3. epigenetic deregulation, in chondrosarcoma, chondroblastoma, and other tumors; 4. deregulated cell survival and proliferation, due to focal copy number alterations, in dedifferentiated liposarcoma; 5. extreme genomic instability, in conventional osteosarcoma as a representative example of sarcomas with highly complex karyotype.

Keywords: Bone; GIST; Molecular diagnostics; Molecular markers; Sarcoma; Soft tissue tumor.

Figure 1

Copy number profiles of sarcomas with simple genome (top) in comparison with sarcomas with complex genome (bottom), as determined by a next generation sequencing platform. A. Ewing sarcoma affecting a 9 year old boy. Note the simple genomic profile. This tumor harbored a EWSR1-FLI1 fusion, identified by this assay. B. High-risk, spindle cell intestinal GIST in a 60 year old male patient. The tumor harbored a KIT K642E mutation detected by the assay. Note a relatively simple genomic profile, with near-diploid karyotype and loss of chromosomes 1p, 14q, 15q and 22q, characteristic of advanced GIST. C. Undifferentiated pleomorphic sarcoma arising in the deltoid of a 55 year old man and D. Conventional osteosarcoma in the femur of a 7 year old boy: multiple chromosomal gains and losses in a non-recurrent pattern. Both these tumors showed alterations in TP53 (copy number loss and truncating mutations).

Figure 2

Detection of molecular alterations by immunohistochemistry. Chromosomal rearrangements frequently result in overexpression of transcription factors that can be detected by immunohistochemistry. A. Pulmonary epithelioid hemangioendothelioma with WWTR1-CAMTA1 fusion, composed of small tumor nodules growing along the preexistent alveolar spaces. B. Cords and strands of endothelial epithelioid cells, with intracytoplasmic lumina, embedded in a myxohyaline stroma characteristic of epithelioid hemangioendothelioma. C. CAMTA1 expression in epithelioid hemangioendothelioma with WWTR1-CAMTA1 gene fusion. D. YAP1-TFE3-rearranged epithelioid hemangioendothelioma; TFE3 overexpression can be detected by immunohistochemistry in this unusually vasoformative variant of epithelioid hemangioendothelioma.

Figure 3

A. KIT mutations in untreated GISTs involve exons 11, 9, 13, and 17, encoding regions of the extracellular, juxtamembrane, ATP-binding pocket, and activation loop domains, respectively. PDGFRA mutations, found in <10% of GISTs, involve analogous domains. B. Relative frequency of the most common KIT and PDGFRA primary mutations in GIST.

Figure 4

Molecular metabolic aberrations leading to epigenetic deregulation. A. Detection of R132H mutant IDH1 in chondrosarcoma. Note that this antibody only detects the specific R132H mutation, which is, in contrast to gliomas where it is the most common mutation, infrequent in chondrosarcoma. Thus, negative immunohistochemistry does not rule out a mutation in IDH1. B. Low magnification view of SDH-deficient gastric GIST, demonstrating its characteristic multinodular growth pattern. C. Epithelioid cytomorphology and D. loss of SDHB expression in SDH-deficient gastric GIST.

Figure 5

High copy number gain of MDM2 and CDK4, in two independent amplicons, in chromosomal region 12q13-15. This lesion was a dedifferentiated liposarcoma with spindle cell and pleomorphic morphologies, arising in a well-differentiated liposarcoma in the inguinal region of a 72 year old male.