Single cell multi-omics analysis of chromothriptic medulloblastoma highlights genomic and transcriptomic consequences of genome instability

Chromothripsis is a form of genome instability, whereby a presumably single catastrophic event generates extensive genomic rearrangements of one or few chromosome(s). However, little is known about the heterogeneity of chromothripsis across different clones from the same tumor, as well as changes in response to treatment. We analyzed single-cell genomic and transcriptomic alterations linked with chromothripsis in human p53-deficient medulloblastoma (n=7). We reconstructed the order of somatic events, identified early alterations likely linked to chromothripsis and depicted the contribution of chromothripsis to malignancy. We characterized subclonal variation of chromothripsis and its effects on double-minute chromosomes, cancer drivers and putatively druggable targets. Furthermore, we highlighted the causative role and the fitness consequences of specific rearrangements in neural progenitors.

FLT3 Amplification as Double Minute Chromosomes in a Patient with Chronic Myelomonocytic Leukemia

Double minute chromosomes (dmins) are a form of gene amplification presenting as small spherical paired chromatin bodies. Dmins are rare in hematologic malignancies and are generally associated with a poor prognosis. Some case reports identified MYC or MLL gene amplification performing as dmin in myeloid neoplasms. FLT3 (FMS-related tyrosine kinase 3) acts as an oncogene in myeloid neoplasms which is associated with several signal transduction pathways. Genomic amplification of FLT3 has not been reported in hematological disease. The current study attempts to demonstrate the existence of double minute chromosomes via FLT3 gene amplification in a patient diagnosed with chronic myelomonocytic leukemia (CMML). Routine G-banded karyotype, array-based comparative genomic hybridization, and fluorescence in situ hybridization analyses were used to characterize the cytogenetic abnormality in the patient’s bone marrow. FLT3 amplification as dmins in a patient with CMML was revealed. This case study reports a rare double minute chromosome via FLT3 amplification in CMML by using array-based comparative genomic hybridization and fluorescence in situ hybridization analyses. The study also proposed another possible mechanism of FLT3 genes in leukemogenesis.