Faculty, Staff and Student Publications
Publication Date
10-1-2024
Journal
Oncogene
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 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.
Keywords
Female, Humans, Embryonic Development, Kidney Neoplasms, Mechanistic Target of Rapamycin Complex 1, Mutation, Phylogeny, TOR Serine-Threonine Kinases, Young Adult, Adult, Middle Aged
DOI
10.1038/s41388-024-03137-7
PMID
39271965
PMCID
PMC11518995
PubMedCentral® Posted Date
9-13-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons