Genomic profiling of neural tumors – implementation into clinical diagnostics for precision care
Solid neural tumors, e.g. those of the central nervous system (CNS) are currently the leading cause of cancer-related mortality and morbidity in children. Among adults, primary brain tumors are the sixth most frequent form of all cancers. The diagnosis of neuroendocrine tumors e.g. pheochromocytoma/ paraganglioma (PPGL) is also very important, as they are associated with hypertension syndrome and high cardiovascular morbidity and mortality. In a variety of cancer types, the identification of tumor-driving mutations and subtype specific variants has been a critical initiating step in the path towards targeted therapy.
The growing need to simultaneously interrogate a large number of loci within a clinically relevant time-frame has directed a shift towards next generation sequencing (NGS). Clinical genomics has the potential to refine tumor classification, stratify patients into treatment groups, identify malignancy markers and druggable targets, and allow treatment follow-up via tumor-specific biomarkers.
Our research aim is to dissect the underlying molecular mechanisms and pathways in tumor progression in neural tumor types from a Swedish cohort. By NGS and microarray analysis, the genomic profile and mutation status from CNS- and PPGL tumors are mapped.
The powerful NGS technology is utilized to generate genomic profiles of each patient’s RNA and DNA, forming the basis for molecular diagnostics and the search druggable targets. The many molecular similarities between neural tumor types also encouraged us to use an integrative approach to identify common underlying mechanisms and core signaling pathways in progression.
Specific aims are:
(1) search for structural variations in pediatric neural tumors, e.g. gene fusions and splice-site alterations, through RNA-sequencing.
(2) map germline and somatic progression-associated DNA variants (single nucleotide variants, indels), structural variants, and copy-number changes through whole genome sequencing
(3) define core signaling pathways and prognostic markers by integrative analyses of whole transcriptome expression profiles
(4) functionally validate the downstream effect of mutations and fusion genes.
The feasibility of this project is based on a strong network of collaborators spanning from the clinic to advanced bioinformatics and experimental medicine. Our research will gain fundamental knowledge of tumor development and improve risk assessment for patients with neural tumors. Incorporation of genomic information in ongoing neuro-oncology diagnostics and planned clinical trials is expected to lead to improved outcomes and result in precision medicine for patients with CNS and peripheral nervous system (PNS) malignancies.