Both benign and malignant bone neoplasms are the product of myriad molecular aberrations. At some fundamental level, the molecular perturbations present in any neoplasm disrupt or enhance the normal pathways that define a cell’s character, including tissue traits, speed of growth, and responsiveness to signals from neighboring cells or circulating factors.
Despite the increasing complexity of cellular pathways involved in cell growth, proliferation, and differentiation, the central tenet of oncogenic transformation involves the collective dysregulation of 7 key regulatory cell pathways: self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis, limitless replicative potential, angiogenesis, metastasis and tissue invasion, and immune evasion.1,2 Subtle differences in how these essential pathways are disrupted dictates the various biological attributes of different benign and malignant neoplasms, and greatly influences clinical variation among different patients with an identical diagnosis.
Perhaps because of limits in current understanding, neoplasia is considered to be a genetic disease process. Neoplastic cells will ultimately display different tissue traits, speed of growth, or responsiveness to outside signals because they express different levels of certain proteins or express uniquely altered proteins that gain non-native functions. These proteins all derive from genes, leading to an understanding of neoplasia and oncogenic transformation primarily through genes.
Much investigational effort in the past decade has elucidated a variety of mechanisms to impact gene expression. Certainly some neoplastic genetic aberrations derive from deleterious alterations in the genetic code itself, such as gene mutations, amplifications, deletions, or higher-order events that alter chromosomes, but many more are likely dysregulated through nongenetic or epigenetic mechanisms, such as micro-RNAs or chromatin remodeling. Historically, as much was learned about the genes lost specifically in cancer cells by studying the germline genetics of heritable cancer predisposition syndromes 20 years ago, most of the nongenetic molecular mechanisms at work in neoplasia is understood by translating each mechanism into the more tractable language of which genes or pathways each upregulates or downregulates.
Currently, none of these not-strictly-genetic molecular mechanisms that are likely at work in neoplasia have even approached clinical importance in the field of bone tumors; although they probably will in the future, this review focuses on genes instead. Even the application of genetic knowledge to bone tumors strays deeply into the research realm and away from clinical standards and practices. For each specific genetic association discussed, it will be made clear which have clinical implications currently or in the foreseeable future. Study of the other lesser-understood genetic associations focuses on the hope that understanding the genetic mechanisms of disease will highlight improved targets for therapy or diagnostic testing.
The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
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