Editorial: Global Approaches to Molecular Diagnosis of Pediatric Cancer

Jeremy Wang ^* Thomas Alexander ^*

• University of North Carolina at Chapel Hill, Chapel Hill, United States

During conversations with nearly every parent of a child with cancer, oncologists must acknowledge the uncertainty about whether a child’s cancer will respond to the treatment prescribed. Our prognostic abilities have improved in settings where molecular testing is available, but crippling uncertainty about treatment response remains, emphasizing the depth of biology that we have yet to uncover. In this research topic, we present articles that cover a range of research types, each relying on molecular diagnostic approaches, to work toward better tools and knowledge for clinicians and their patients.For extremely rare tumors and presentations, case reports with literature reviews offer initial suggestions of natural history, prognosis, and molecular alterations. Pellegrino et al demonstrate this through a case report of malignant ectomesenchymoma, calling attention to the frequency of HRAS mutations (in this instance found through whole exome sequencing) in this biphenotypic tumor type with features of mesenchymal and neuroectodermal elements. In a similar type of report, Ogawa et al describe an unusual case of an atypical lipomatous tumor, with the diagnosis supported by the identification of MDM2 amplification on fluorescence in situ hybridization. In both cases, molecular findings support the final diagnosis. However, the molecular results are not required to complete the diagnosis, and are not fully specific for each diagnosis, highlighting the challenge for pathologists to determine appropriate molecular evaluations for various pediatric tumors. The next set of articles focuses on molecular-based translational research, assessing potential prognostic markers and cancer vulnerabilities. Braghini et al present research that relies on knowledge of potential therapeutic targets in hepatocellular carcinoma to explore similar pathways in hepatoblastoma. Their early in vitro data suggest that overexpression and activation of focal adhesin kinase (FAK) occurs in hepatoblastoma, and inhibition of this pathway can slow proliferation and induce apoptosis of cell lines. This early work must be followed by expanded research with larger cohorts of hepatoblastoma and in vivo models. Other efforts to explore new biomarkers of prognosis and targets focus exosomes and telomere biology. Bhavsar et al presents a review describing recent progress in understanding and exploiting exosomes in tumor biology. With a focus on neuroblastoma, the authors emphasize the growing literature utilizing exosomes as potential circulating biomarkers and therapeutic vehicles for precision tumor treatment and vaccination. Similarly, Burrow et al summarize data about telomere biology as potential prognostic markers with potential therapeutic implications. Using a highly sensitive rtPCR-based C-circle assay (CCA) to detect alternative lengthening of telomeres (ALT), they characterize the prevalence and clinicopathological association of ALT in pediatric sarcomas.For most cancer types, molecular testing is required for complete clinical classification to inform prognosis and therapeutic decision-making. Even so, questions about the “what” and “how” of molecular testing for clinical care are complex. What technical assay should be used with which computational algorithm? How can the global community commit to equitable access of molecular diagnostic tools? The last two articles in this collection speak to some of these implementation challenges.Skitchenko et al highlight the analytical challenges of nontargeted genomic sequencing. They assessed germline predisposition to cancer for a child with medulloblastoma. They used whole exome sequencing results taken through two different analytical pipelines. The pipelines provided discrepant clinically relevant results, based upon computational differences as opposed to any technical concerns about the sequencing. While their case description does not provide a solution to the challenge of implementation of computational tools, they shine an important light on the need for ongoing expert discussion to determine necessary validation steps for computationally heavy diagnostic assays.Finally, Gastier-Foster et al demonstrated the potential of the NanoString nCounter system as a targeted fusion detection approach for acute leukemia in Malawi. They demonstrate that this technology can be utilized in a low-income country and that it would provide clinically important diagnostic information beyond the current standard of care testing. Their work is an important contribution to efforts to overcome diagnostic limitations in resource-limited settings. These findings also raise two critical challenges in the implementation of advanced molecular testing specific to low-resource settings: How should molecular tests be validated locally when the “truth” of the sample is not available? How do we consider the scalability and sustainability of a new test at the outset of clinical validation?The collection of papers in this research collection shows exciting progress ranging from improved molecular description of exceedingly rare tumors to identification of additional biomarkers with potential for future clinical use to advancing the conversations about clinical use of new molecular assays and analytic tools. Ongoing needs from the community of pediatric cancer researchers, pathologists, and hospital administrators include (1) continued identification of molecular biomarkers for risk stratification and identification of therapeutic vulnerabilities, (2) development of rational recommendations for clinical molecular testing for different tumor types, potentially with resource-adapted guidance, and (3) a global commitment to implementation of molecular testing across different resource settings.