Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis
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 using whole genome sequencing alongside single cell and bulk transcriptomic sequencing. Phylogenetic reconstruction timed the origin of all tumours to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Biochemical and structural analysis of their shared MTOR mutation, absent from normal tissues, demonstrates enhanced protein flexibility, enabling 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.
Authors
- Madhanagopal Anandapadamanaban (ORCID: https://orcid.org/0000-0002-4237-0048)
- Olga Perišić (ORCID: https://orcid.org/0000-0002-3842-2896)
- Roger Williams (ORCID: https://orcid.org/0000-0001-7754-4207)
- Ruoyan Li (ORCID: https://orcid.org/0000-0001-5337-9729)
- Peter J. Campbell (ORCID: https://orcid.org/0000-0002-3921-0510)
- Kevin W. Loudon (ORCID: https://orcid.org/0000-0001-9055-6894)
- Sarah Amalia Teichmann (ORCID: https://orcid.org/0000-0002-6294-6366)
- Laura Allen (ORCID: https://orcid.org/0000-0002-2033-7298)
- Anne Y. Warren (ORCID: https://orcid.org/0000-0002-1170-7867)
- Sam Behjati (ORCID: https://orcid.org/0000-0002-6600-7665)
- Iain M. Hay (ORCID: https://orcid.org/0000-0002-5451-1768)
- Yvette Hooks
- Grant Duncan Stewart (ORCID: https://orcid.org/0000-0003-3188-9140)
- Menna Ruth Clatworthy (ORCID: https://orcid.org/0000-0002-3340-9828)
- Matthew H V Byrne (ORCID: https://orcid.org/0000-0002-2414-352X)
- Kirsty Roberts (ORCID: https://orcid.org/0000-0003-0765-3752)
- Thomas J. Mitchell (ORCID: https://orcid.org/0000-0003-0761-9503)
- Clarissa N. Pacyna (ORCID: https://orcid.org/0000-0002-4404-8183)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- MRC Laboratory of Molecular Biology (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
Publication Details
- Journal
- Oncogene
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1038/s41388-024-03137-7
- Citations
- 3
- Primary Topic
- Renal and related cancers
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- Wellcome Trust
- UK Research and Innovation
- Marshall Aid Commemoration Commission
- Cancer Research UK
- Medical Research Council