Development of novel spatial genomics approaches to visualize mutant clones in normal human tissues

Tue, 31 Mar 2026 09:00:00 +0200

Somatic mutations accumulate in the genome of dividing cells, occasionally leading to a cellular fitness advantage and positive selection. This fitness advantage results in small clones, driven by point mutations in common cancer-related genes such as TP53 and NOTCH1, similar to those seen in malignant tumors. Determining the role of these clones in human carcinogenesis requires the direct visualization of their mutations in the spatial context.

Existing technologies are restricted to gene expression profiles (spatial transcriptomics), lacking the exact genetic sequence. Therefore, we aim to develop a novel sequencing-based spatial genomics platform relying on custom in-situ synthesized microarrays. These arrays contain spatially-barcoded oligonucleotides at high spot-resolution.

We are currently optimizing this platform to enable full-length whole-transcriptome sequencing. The oligonucleotides are modified to capture mRNA molecules, followed by a library preparation compatible with Oxford Nanopore Technologies long-read sequencing devices. During the library preparation, the transcriptome can be enriched for genes of interest such as TP53. We will then detect somatic mutations using dedicated long-read RNA variant callers. In a second approach, we aim to modify the barcoded capture probe to target preidentified mutations at the DNA-level. By ligating a pool of target-specific oligonucleotides to the array, we plan on targeting multiple gene-regions of interest.

The application of this novel technology to human epithelial tissues will potentiate the analysis of clonal interaction patterns and determine the role of clonal competition in human carcinogenesis.

long-read sequencing | OncoRNALab

Development of novel spatial genomics approaches to visualize mutant clones in normal human tissues