Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis

Pacyna, C. N.; Anandapadamanaban, M.; Loudon, K. W.; Hay, I. M.; Perisic, O.; Li, R.; Byrne, M.; Allen, L.; Roberts, K.; Hooks, Y.; Warren, A. Y.; Stewart, G. D.; Clatworthy, M. R.; Teichmann, S.; Behjati, S.; Campbell, P. J.; Williams, R. L.; Mitchell, T. J.

doi:10.1101/2023.12.12.570785

bioRxiv · 10.1101/2023.12.12.570785

Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis

Pacyna, C. N.·Anandapadamanaban, M.·Loudon, K. W.·Hay, I. M.·Perisic, O.·Li, R.·Byrne, M.·Allen, L.·Roberts, K.·Hooks, Y.·Warren, A. Y.·Stewart, G. D.·Clatworthy, M. R.·Teichmann, S.·Behjati, S.·Campbell, P. J.·Williams, R. L.·Mitchell, T. J.

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Abstract

Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl, timing their shared origin to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Their shared MTOR mutation, absent from normal tissues, enhances protein flexibility, which enables a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.

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Pacyna, C. N., Anandapadamanaban, M., Loudon, K. W., Hay, I. M., Perisic, O., Li, R., Byrne, M., Allen, L., Roberts, K., Hooks, Y., Warren, A. Y., Stewart, G. D., Clatworthy, M. R., Teichmann, S., Behjati, S., Campbell, P. J., Williams, R. L., Mitchell, T. J.. 2023-12-13. Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis. https://doi.org/10.1101/2023.12.12.570785

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