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Pathogenetic factors in soft tissue and bone sarcomas

Thomas F DeLaney, MD
David G Kirsch, MD, PhD
Section Editors
Robert Maki, MD, PhD
Raphael E Pollock, MD
Deputy Editor
Diane MF Savarese, MD


Sarcomas are malignant tumors arising from skeletal and extraskeletal connective tissues including the peripheral nervous system. Approximately 76 percent arise in soft tissue and the remainder in bone.

There is no clearly defined etiology in most cases of soft tissue sarcoma, but a number of associated or predisposing factors have been identified [1]. These include a genetic predisposition, gene mutations, radiation therapy (RT), chemotherapy, chemical carcinogens, chronic irritation, and lymphedema. In addition, an association between viral infection and sarcoma has been shown for HIV and human herpesvirus 8 in Kaposi sarcoma, and for Epstein-Barr virus (EBV) and smooth muscle tumors in immunocompromised patients.


Some patients with bone and soft tissue sarcomas, particularly children, have a genetic predisposition to cancer [1-5]. In some cases, individuals are from families with a defined inherited predisposing condition, such as Li-Fraumeni syndrome (LFS) or retinoblastoma, but many cases do not fit recognized inherited cancer syndromes. One analysis, in which 1162 patients with sarcoma, unselected for family history, underwent targeted exon sequencing of 72 genes selected for their association with cancer risk, concluded that approximately one-half of the patients had putatively pathogenic, monogenic, and polygenic variation in known and novel cancer genes [6]. In a pooled analysis of all sarcoma probands, 240 carried multiple variants, suggesting a polygenic contribution to sarcoma risk. Only 155 (17 percent) of the 911 families with informative pedigrees fit recognizable cancer syndromes.

The major genetic syndromes are briefly outlined below.

Li-Fraumeni syndrome — Mutations in TP53 are the most common germline mutations that predispose to pediatric sarcomas, including osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma [5]. As many as 7 percent of children with soft tissue sarcomas may have LFS [7]. In a series of 151 children with soft tissue sarcomas, for example, five of the families (3.3 percent) manifested the classic LFS familial cancer syndrome, 10 (6.6 percent) had features consistent with the syndrome, and 16 (10.5 percent) had one parent with a possible hereditary cancer syndrome or with cancer before the age of 60 [4].


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