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

Area of Science:

• Developmental biology
• Cancer genomics
• Molecular oncology

Background:

• Embryogenesis is a critical developmental period where mutations can lead to widespread disease-predisposed cells.
• Paediatric tumours often arise from early developmental errors, but their precise origins and genetic drivers can be challenging to ascertain.
• Understanding the evolutionary trajectory of synchronous tumours is crucial for effective clinical management.

Purpose of the Study:

• To investigate the evolutionary history and molecular underpinnings of synchronous renal tumours in a paediatric patient.
• To determine the cell of origin and timing of tumour initiation during embryogenesis.
• To characterize the functional impact of a shared mutation on key cellular pathways.

Main Methods:

• Whole genome sequencing of synchronous renal tumours.
• Single-cell and bulk transcriptomic sequencing.
• Phylogenetic reconstruction to determine tumour evolutionary history.
• Biochemical and structural analysis of identified mutations.

Main Results:

• Phylogenetic analysis traced the origin of four synchronous renal tumours to a single multipotent embryonic cell in the right kidney around 4 weeks post-conception.
• A shared mutation in the MTOR gene was identified in all tumours and absent in normal tissues.
• The MTOR mutation was shown to enhance protein flexibility, leading to significantly increased activity of mTORC1 and mTORC2 signalling pathways.
• This mutation is not typically detected by standard genetic screening methods.

Conclusions:

• Developmental mutations, even those undetectable by conventional screening, play a critical role in paediatric tumour formation.
• The identified MTOR mutation drives tumourigenesis by dysregulating mTORC1/mTORC2 signalling.
• Characterizing the evolutionary history and molecular basis of paediatric tumours is essential for prognosis, targeted therapy, and family screening.