Clonal evolution during metastatic spread in high-risk neuroblastoma

Abstract

High-risk neuroblastoma is generally metastatic and often lethal. Using genomic profiling of 470 sequential and spatially separated samples from 283 patients, we characterize subtype-specific genetic evolutionary trajectories from diagnosis, through progression and end-stage metastatic disease. Clonal tracing timed disease initiation to embryogenesis. Continuous acquisition of structural variants at disease defining loci (MYCN, TERT, MDM2-CDK4) followed by convergent evolution of mutations targeting shared pathways emerged as the predominant feature of progression. At diagnosis metastatic clones were already established at distant sites where they could stay dormant, only to cause relapses years later and spread via metastasis-to-metastasis and polyclonal seeding after therapy.

A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations

“…Moreover, chr17q/1q gains were found to enhance the MYCN -driven differentiation block and acquisition of tumourigenic hallmarks such as proliferation, clonogenicity and resistance to apoptosis. In line with recent studies 29,89 , we speculate that CNAs provide an early selective advantage manifested by the expansion of undifferentiated cells, which act subsequently as a NB-initiating entity upon a second oncogenic hit such as MYCN overexpression.…”

“…Our detailed genetic analyses of the used cell lines revealed other mutations that had naturally arisen in these cell lines ( Supplementary Table 4 ), including a point mutation in the BCL6-interacting corepressor BCOR ( BCOR L1673F ). BCOR mutations have been previously observed in human induced pluripotent stem cell cultures 95,96 and NB patients with BCOR mutations exhibit a high frequency of CNAs 89 . BCOR mutations have also been reported together with CNAs in other cancers, e.g., retinoblastoma 97 .…”

Nuclear factor-κB activation by transforming growth factor-β1 drives tumour microenvironment-mediated drug resistance in neuroblastoma

“…Approximately fifty percent of the children diagnosed with NB are classified as having a high-risk cancer based on the stage of disease and biological features, including amplification of the MYCN oncogene (MYCN-A), loss or gain of genetic material, age at diagnosis, and presence of unfavourable histological features. Despite an intensive treatment with a combination of surgery, myeloablative chemotherapy, radiation therapy and immunotherapy, more than 50% of these children succumb to refractory or recurrent disease [ 6 , 7 ]. The underlying mechanisms of chemotherapy resistance in NB are complex.…”