Pediatric solid tumor genomics and developmental pliancy

Abstract

Pediatric solid tumors are remarkably diverse in their cellular origins, developmental timing and clinical features. Over the last 5 years, there have been significant advances in our understanding of the genetic lesions that contribute to the initiation and progression of pediatric solid tumors. To date, over 1000 pediatric solid tumors have been analyzed by Next-Generation Sequencing. These genomic data provide the foundation to launch new research efforts to address one of the fundamental questions in cancer biology-why are some cells more susceptible to malignant transformation by particular genetic lesions at discrete developmental stages than others? Because of their developmental, molecular, cellular and genetic diversity, pediatric solid tumors provide an ideal platform to begin to answer this question. In this review, we highlight the diversity of pediatric solid tumors and provide a new framework for studying the cellular and developmental origins of pediatric cancer. We also introduce a new unifying concept called cellular pliancy as a possible explanation for susceptibility to cancer and the developmental origins of pediatric solid tumors.

Figure 1

Pediatric solid tumors have diverse developmental origins. Unlike hematologic malignancies and brain tumors, pediatric solid tumors can arise from any of the three germ layers in the embryo. Representative examples are highlighted for each lineage.

Figure 2

Pediatric solid tumors have diverse cellular origins with unique genetic lesions. (a) A simplified lineage diagram for several mesodermally derived lineages including those relevant to pediatric solid tumors such as bone, muscle and adipose. It is not known which cell lineages or stages are the origins of pediatric solid tumors and there are several alternative models. (b) If the genetic lesions occur at equal frequency across cellular lineages and developmental stages, then one model predicts that particular cells at distinct stages of development are more susceptible to malignant transformation than others. In this example, hedgehog pathway mutations only lead to malignant transformation in the adipose lineage and those cells adopt differentiated features of muscle. Thus, one cannot necessarily infer the cell of origin based on the differentiation features of the tumor itself. (c) The susceptibility to malignant transformation is pathway-dependent. The same adipose lineage is not susceptible to malignant transformation following oncogenic activation of the RAS pathway in this model. Instead, it is the muscle lineage that gives rise to RAS mutant tumors. Only by studying the developmental origins of pediatric solid tumors can we begin to elucidate the cell and developmental stage-specific susceptibility to individual oncogenic lesions.