PATH-10. Nanopore sequencing reveals novel ALK fusion with interposed element in a neonate with hemispheric glioma

Abstract

Abstract Here we describe the clinical course and unique molecular findings in a female neonate with infantile hemispheric glioma (IHG). The patient presented at the age of 17 days with macrocephaly and suboptimal weight gain. MRI brain revealed an 8.5cm mass over the right frontal region with significant mass effect and entrapment of ventricles. Urgent ventriculoperitoneal shunt insertion and biopsy of the highly vascular lesion was performed. Pathology was compatible with glioblastoma multiforme. Methylation profiling classified the sample as inflammatory tumor tissue (MNP v11b4), while panel RNA-sequencing revealed a fusion event between HMBOX1 and ALK which has not been described in primary CNS tumors. Long-read sequencing with the Nanopore system further revealed complex genomic rearrangement involving an interposed genomic fragment from a third chromosome with validation by Sanger sequencing. Based on an integrated diagnosis of IHG, the patient went on to receive neoadjuvant chemotherapy per the CNS-14 protocol (cyclophosphamide, carboplatin, etoposide) with significant tumor shrinkage. Near total removal of the lesion was achieved after 4 cycles of chemotherapy and adjuvant treatment with 4 additional cycles was given. The patient tolerated therapy well other than self-limiting transaminitis. At the end of treatment, the patient enjoyed intact neurology and satisfactory developmental progress. Our case report illustrates the value a multi-pronged approach to characterizing rare pediatric CNS tumors. The precise delineation of breakpoints in fusion-driven tumors might be of value in the design of cfDNA-based assays. (APYL and CTLC contributed equally to the submission)