Translational case studies from Early Cancer Institute Scientists

The first steps towards cancer are often long before diagnosis.  Recent findings from a collaborative team across the Early Cancer Institute, the Sanger Institute, and the MRC Laboratory of Molecular Biology highlight that these first steps can happen well before birth. By identifying the mutations in the embryo driving a teenager’s four renal tumours, this study not only highlights the frontiers of early detection but also has already had strong clinical benefit for this young patient and her family.

A teenage girl was diagnosed with four tumours spread throughout her right kidney as an incidental finding.  Following surgical removal of the kidney (nephrectomy) examination of the tissue revealed that two of the tumours were noncancerous growths and two were a rare type of kidney cancer, malignant chromophobe renal cell carcinomas (chRCC). Because these tumour types are exceedingly uncommon in children and because multifocal tumours are usually indicative of a germline mutation – a change to DNA inherited during conception that predisposes to cancer - the patient was referred to the clinical genetics team for standard testing. However, no causative germline mutation was identified, so the girl and her siblings were placed on an intensive screening protocol in case the mutation that caused the patient’s tumours was shared across the entire family.

To search for the underlying cause of this patient’s disease, a team at the Early Cancer Institute and the Wellcome Sanger Institute, led by ECI faculty Mr Tom Mitchell and PhD student Chloe Pacyna, used whole genome sequencing to uncover that each of the four tumours had hundreds of independently acquired mutations with unique chromosomal copy number profiles.  However, the tumours also shared 15 mutations, including a 12-base pair, in-frame duplication mutation in a recognised cancer gene known as MTOR.

This MTOR mutation was absent from blood and histologically normal kidney samples. Based on previous foetal somatic mutation studies, the team could use the small number of shared mutations to time when the MTOR mutation occurred, uncovering that this causative event happened around the fourth week of embryogenesis, when embryonic kidney progenitors, called nephrogenic cords, divide to start to form the kidney.

This revealed that the putative driver mutation for these four tumours was acquired very early in development and hitchhiked along developmental pathways to seed affected cells throughout the right kidney.

In addition to DNA studies, the group also sequenced both bulk and single cell RNA from this patient’s biopsy samples, highlighting that each tumour was transcriptionally similar to distinct normal renal cell types, including collecting duct type A cells, distal principal cells, and loop of Henle cells. These findings suggest that the developmental renal progenitor cell that acquired the MTOR mutation was sufficiently multipotent to generate histologically and transcriptomically unique tumours.

Because the MTOR mutation had not before been seen in other patients, the team wanted to be fully confident that this mutation was the initial cause of this girl’s tumours. Structural biologist Dr Roger Williams and postdoctoral fellow Dr Madhan Anandapadamanaban at the Laboratory of Molecular Biology, Cambridge, undertook further research and their findings strongly suggest that the embryonic MTOR mutation was the “first hit” in causing this patient’s tumours.

These research efforts have had an immediate translational impact on the care of this patient and her family. The causative mutation was acquired in utero, not inherited from parental DNA, so the patient’s siblings have no added risk of developing similar tumours in the future. Additionally, because the mosaic MTOR mutation occurred around the fourth week of embryogenesis such that all predisposed cells were expected to be limited to the removed kidney, the patient is unlikely to reoccur. In sharing these findings with the patient’s clinical team, her family’s clinical management has been adjusted, preventing unnecessary lifelong screening of her siblings and bringing greater reassurance to the patient and her family that she won’t likely develop further related tumours. 

Though this study has focused on just one individual patient, its impact stretches far beyond her immediate family. The case study adds to a small but growing number of cases of tumours caused by mutations acquired in embryogenesis.  These mutations can cause unique patterns of cancer predisposition and disease, depending on the timing, the cell, and the location at which the mutation occurs. In addition to bringing greater attention to these cases, the project highlights the clinical utility of whole genome sequencing in identifying tumorigenic developmental mutations when standard clinical genetic screens fail to identify the cause of multifocal disease. We look forward to undertaking further studies on the potential tumourigenic role of developmental mutations to better understand their role in pathogenesis and to improve clinical management of affected patients.