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Multi-omics study helps unravel how germ cell tumours develop and differentiate

Written by Miyako Rogers, Science Writer

A new study investigates the origins and development of germ cell tumours (GCT), which are derived from primordial germ cells (PGC). Researchers revealed that these tumours use similar growth pathways to normal tissues, and identified genetic features that can be traced back to foetal development in the womb. They also showed that GCTs carry distinct mutational signatures in children versus adults. These signatures highlight differences in the developmental timing of mutations in children and could be used as a biomarker to help inform cancer treatment.

Germ cell tumours

Germ cell tumours are one of the most common types of cancer in adolescents and young men and makeup 5% of all childhood cancers. While they usually occur in the testes or ovaries, they are also sometimes found in the abdomen, brain, chest and even teeth. These tumours are derived from PGCs but can develop into many different cell types, making them uniquely able to repeat developmental processes that occur in the womb. In this study, researchers collected GCT samples from 15 individuals aged 1-58 years. These tumours were then micro-dissected using a laser to excise 547 distinct histological units. These units were analysed using whole-genome sequencing to investigate their mutational profile.

Foetal origins

Researchers compared GCT development to normal tissue growth and found that these pathways mirror normal tissue development. However, researchers found that GCTs differ from normal tissues in one very specific way: Foetal development transcripts are retained in GCTs. This means that despite variation in the cell type and age of GCTs, researchers can trace certain features of GCT mutational profiles back to genetic events that occur during foetal development. One such feature they identified was whole genome duplication (WGD), a genetic event that initiates GCT development. While WGD is preserved in the genomes of all GCTs, researchers did find a difference between pre- and post-pubertal tumours.

Differences pre- and post-puberty

Researchers discovered that the developmental timing of WGD varies between pre- and post-pubertal GCTs. This difference could explain why researchers observed that tumours in children below the age of 12 have distinct mutational signatures. A lot of adolescent and child patients with GCT fall very close to the border between paediatric and adult treatment protocols. Chronological age doesn’t always line up exactly with their “true” biological age; as a result, some patients on the borderline may not receive the most appropriate treatment. These mutational signatures could act as potential biomarkers which could define a subset of GCTs as paediatric tumours, thus informing clinicians on which treatment option is most suitable.

In conclusion, while this study only investigated GCTs, this approach could be applied across different human cancers to help identify genetic hallmarks of development and initiation. The mutational signatures identified in paediatric GCTs has clinical applications and could be used as biomarkers to help inform treatment strategies.

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Cancer / Genomics