Sarcomas, cancers of mesenchymal tissues, remain challenging diseases to treat. Sarcomas are rare cancers, and directly affect a small portion of the general population(1
). However, their impact is heightened by their deadly incidence among adolescents and young adults.
Mesenchymal tissues line neither the body surface nor ingesting/inhaling organ cavities exposed directly to environmental toxins. The development of cancer in mesenchyme therefore may depend more on biologically intrinsic factors than environmental exposures. This thought is supported by the relative rarity of sarcomas, despite the fact that mesenchymal tissues comprise a strong majority of tissue volumes and body mass percentages in the human body(2
). The major determinant of tissue-intrinsic characteristics beyond the chance accrual of replication errors, mis-recombinations, and erroneous chromosomal segregations, is the inherited genome from which each cell begins. This raises the possibility for heritable risks for sarcomagenesis.
The major challenge to studying the familiality of sarcoma is its scarcity in the general population. If the brother or sister of a sarcoma patient had even a 5-fold relative risk for sarcoma, that risk would not be readily detected unless the patient had tens or hundreds of thousands of siblings. The Utah population database (UPDB) has proven valuable to the study of heritability, especially for rare diseases, given the depth of genealogies recorded and its careful linking to the Utah Cancer Registry (UCR), which is part of the Surveillance, Epidemiology and End Results (SEER) Program and has been maintained for the last 50 years(3
). Nonetheless, an investigation of familiality for any individual subtype of sarcoma is likely to be underpowered even over this 50-year population accrual due to insufficient case numbers. A potential route forward from this challenge is the meaningful grouping of sarcoma subtypes. While individual sarcoma subtypes tend to derive their identities from known or presumed tissues of origin, there is a variety of ways to lump subtypes together. For example, sarcomas may be grouped according to the population affected, adolescents and young adults versus the elderly. Alternatively, they can be grouped according to bone versus soft-tissue locations; many current treatment paradigms roughly follow this crude grouping, with chemotherapeutic adjuvants for bone sarcomas and adjuvant radiation for soft-tissue sarcomas, generally.
Sarcomas can also be classified according to tumor cell genetics. Many are associated with balanced chromosomal translocations, which generate subtype specific fusion oncogenes, such as EWS-FLI1 in Ewing’s sarcoma and SYT-SSX1 in synovial sarcoma(4
). Other sarcomas can be termed complex karyotype sarcomas. This latter group exhibits genomic and chromosomal instability, with mutations and copy number alterations common throughout the genome and wild non-diploid karyotypes frequent(4
). Familiality has been suspected, but not proven, for both types of sarcoma. It has been most carefully explored in the bone sarcomas, osteosarcoma and Ewing’s sarcoma.
Osteosarcoma, the prototype complex genotype sarcoma, arises more frequently in three heritable Mendelian cancer predisposition syndromes, Li Fraumeni(5
), hereditary retinoblastoma(6
), and Rothmund Thompson syndrome(7
). However, these syndromes contribute only a scant number of cases to the overall population incidence of osteosarcoma. Beyond these sydnromes, there may be other complex heritable predispositions not yet recognized that engender the genomic instability resulting in complex genotype sarcomas like osteosarcoma.
Ewing’s sarcoma, the most common balanced translocation-associated sarcoma does not arise commonly in any heritable cancer predisposition syndrome. Individual cases have been reported following diagnosis and treatment for retinoblastoma(8
). The general association between Ewing’s sarcoma and other cancers in families has been suggested by a few small series only (10
). Four sibling pairs with Ewing’s sarcoma have been described(11
). Ewing’s sarcoma also has been associated in families with both umbilical and inguinal hernias(14
). Finally, Ewing’s sarcoma has a much lower incidence among American individuals of African descent than among Americans of European or Asian ancestry(17
). These epidemiologic findings all suggest a modest but discernable genetic contribution to disease risk, despite the lack of Ewing’s sarcoma with any known hereditary cancer syndrome(18
There are two hypothesized heritable risks for the group of balanced translocation associated sarcomas like Ewing’s sarcoma. First, there may be a heritable predisposition to generate the translocations themselves. Such heritable predispositions to generate translocations could be either generalized or locus (sarcoma sub-type) specific. The latter, are obviously difficult to detect without large numbers of cases and deep genealogies. Second, there may be heritable tendencies for a cell that has undergone such a translocation to complete transformation, rather than apoptose. Silencing of the p53 pathway, for example, is common even among balanced translocation sarcomas(19