30 June 2021

Oncode Investigator Jarno Drost and his team part of joint research that uncovers the cellular signatures of kidney tumors

Oncode Investigator Jarno Drost and his team at the Princess Maxima Centre in collaboration with researchers at the Wellcome Sanger Institute and Great Ormond Street Hospital (GOSH) have uncovered the origins of seven types of kidney cancer including several rare subtypes. Their findings confirm that these cancers have their origin in specific forms of developmental cells present in the maturing fetus. The study has recently been published in Nature Communications.

Peter Thijssen Support Staff

“Many childhood malignancies arise during embryonic development as a consequence of derailed developmental programs. In many cases their cellular origin remains unknown hampering therapeutic innovation” says Jarno Drost.

All cancers are derived from normal cells that have started to multiply uncontrollably. By comparing patterns of gene expression in cancer and normal cells, it is possible to learn about aspects of each tumour’s origin and behaviour. This type of analysis has been made possible by the advent of single-cell mRNA sequencing, a high-resolution technology that can identify different cell types present in a tissue according to the genes expressed by individual cells. “Together with our collaborators from the Wellcome Sanger Institute and Great Ormond Street Hospital, we studied the origins of several childhood kidney tumor subtypes using bulk and single cell RNA-sequencing” adds Drost.

The study used computational methods to analyse existing datasets and pinpoint the ‘cellular signals’ given off by different cancers as they emerge. The method holds promise as a tool for diagnosing patients with rare cancers – in the study, one patient’s cryptic kidney cancer was identified as a Wilms-like tumour by looking at its cellular signals. Previous studies have used these techniques to compare normal and diseased tissue in some of the most common kidney cancers, but to conduct single-cell sequencing on many hundreds of tumours would not be achievable.

In this study, researchers turned to computational techniques to mine Human Cell Atlas (HCA) reference data and databases of tumour gene expression. They assessed mRNA signals in 1,300 childhood and adult renal tumours, spanning seven different tumour types, in order to investigate the origins of these cancers. The results confirmed that these childhood cancers are developmental in origin, occurring after errors in a particular developmental cell type’s journey to maturity. In contrast, adult kidney cancers emerged from mature cell types and do not revert to a developmental pattern of gene expression in the vast majority of cases. Each cancer type was also found to exhibit unique ‘cellular signals’, or patterns of gene expression, that could be used to classify them in future.

The study sheds light on the behaviour and origins of some kidney tumour subtypes whose rarity would have made it difficult to examine otherwise. These were congenital mesoblastic nephroma, clear cell sarcoma of the kidney, malignant rhabdoid tumour of the kidney, and chromophobe renal cell carcinoma. The method pioneered in the study also helped to classify one patient’s tumour, which clinicians had been unable to diagnose fully. “We hope that the developed computational approach can serve as a blueprint for studying the origins of other (rare) tumor entities and that our findings will contribute to the development of improved treatment approaches for children with kidney cancer” concludes Drost.

Read the full article here.

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