Single-cell DNA sequencing identifies risk-associated clonal complexity and evolutionary trajectories in childhood medulloblastoma development

Danilenko, Marina, Zaka, Masood, Keeling, Claire, Crosier, Stephen, Lyman, Stephanie, Finetti, Martina, Williamson, Daniel, Hussain, Rafiqul, Coxhead, Jonathan, Zhou, Peixun, Hill, Rebecca M., Hicks, Debbie, Rand, Vikki, Joshi, Abhijit, Schwalbe, Ed, Bailey, Simon and Clifford, Steven C. (2022) Single-cell DNA sequencing identifies risk-associated clonal complexity and evolutionary trajectories in childhood medulloblastoma development. Acta Neuropathologica, 144 (3). pp. 565-578. ISSN 0001-6322

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Abstract

We reconstructed the natural history and temporal evolution of the most common childhood brain malignancy, medulloblastoma, by single-cell whole-genome sequencing (sc-WGS) of tumours representing its major molecular sub-classes and clinical risk groups. Favourable-risk disease sub-types assessed (MB and infant desmoplastic/nodular MB ) typically comprised a single clone with no evidence of further evolution. In contrast, highest risk sub-classes (MYC-amplified MB and TP53-mutated MB ) were most clonally diverse and displayed gradual evolutionary trajectories. Clinically adopted biomarkers (e.g. chromosome 6/17 aberrations; CTNNB1/TP53 mutations) were typically early-clonal/initiating events, exploitable as targets for early-disease detection; in analyses of spatially distinct tumour regions, a single biopsy was sufficient to assess their status. Importantly, sc-WGS revealed novel events which arise later and/or sub-clonally and more commonly display spatial diversity; their clinical significance and role in disease evolution post-diagnosis now require establishment. These findings reveal diverse modes of tumour initiation and evolution in the major medulloblastoma sub-classes, with pathogenic relevance and clinical potential.

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