Decoding the origins of childhood cancer
Alexandra Avgustinova
Institut de Recerca Sant Joan de Déu and IRB Barcelona
Nearly 25% of all cancers harbour mutations in constituents of the SWI/SNF chromatin remodelling complexes, indicating a potentially functional role of chromatin accessibility dysregulation in oncogenic transformation. Indeed, biallelic inactivation of the SWI/SNF subunit SMARCB1 is a hallmark feature (>95% penetrance) of malignant rhabdoid tumours (MRTs), and constitutes the only recurrent mutation in these tumours. MRTs are remarkably genomically simple tumours: chromosomal aberrations are rare, and their genomic mutation rate is among the lowest of any cancer. Hence, SMARCB1-loss in MRTs is the purest known instance of epigenetically-driven oncogenic transformation. MRTs are highly malignant and heterogeneous paediatric cancers usually diagnosed in infants <2 years of age. Prognosis is abysmal due to fast tumour growth, local invasiveness and metastasis, with 5-year survival of <20%. Current treatment strategies involve a multimodal regimen combining tumour resection, radiotherapy and chemotherapy; the young patient age results in serious long-term sequelae of treatment, including severe motor, visual and cognitive impairment. Moreover, both chemotherapy and radiotherapy are mutagenic, and hence will give rise to clonal tumour heterogeneity in a previously genomically simple tumour, thereby enhancing its evolutionary prowess and resulting in a potentially more complex disease to treat.
Therefore, there is an urgent need to understand the mechanisms of epigenetically-driven malignant transformation to allow for the pursuit of more personalised and less toxic and mutagenic approaches to MRT treatment. Important outstanding questions include: What is the cell-of-origin of MRTs? How does epigenetic reprogramming in this cell-of-origin cause malignant transformation? Can we reverse these epigenomic alterations to trigger terminal differentiation of MRTs?
To answer these questions, we combine state-of-the-art single-cell genomics, spatial transcriptomics, lineage tracing and different childhood cancer in vitro and in vivo models. Based on our findings we hope to unlock targeted treatments for MRT patients.