Preprint: somatic NF1 second-hit mutations show strong clonal selection in oligodendrocyte lineage cells

A preprint posted to bioRxiv reports findings from single-cell genomic profiling of more than 1.7 million individual cells across multiple donors carrying germline pathogenic variants in NF1, the tumour suppressor gene mutated in neurofibromatosis type 1 (NF-1). The study, using combined spatial genotyping and transcriptomics, tracks where and when somatic 'second-hit' loss-of-function mutations in NF1 arise and which cell types retain them.

The core finding is that somatic NF1 second-hit mutations are pervasive across tissues — but positive clonal selection (the process by which a mutated cell out-competes neighbours and expands) is almost entirely restricted to oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs). In neurons and most other cell lineages, NF1 second-hit mutations are exceedingly rare or non-selected. This cell-type specificity in clonal dynamics may help explain why NF-1-associated tumours of the nervous system, particularly optic pathway gliomas and neurofibromas, arise in specific cellular contexts.

The spatial genotyping component allowed the authors to link clonal expansions to their anatomical locations, providing a spatially resolved map of early tumourigenic steps in a cancer predisposition syndrome. The preprint has not been peer-reviewed. Researchers studying NF-1 biology, tumour suppressor function, and the cell-of-origin problem in cancer will find this a substantial dataset. Genetic counsellors supporting NF-1 families may note the mechanistic context this provides for understanding somatic second-hit dynamics, though clinical interpretation is not changed by this preclinical finding.