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New research precisely maps genetic mutations onto malignant and benign prostate tissue

Written by Miyako Rogers, Science Writer

In a new study published in Nature, researchers have created a detailed cross-sectional map of the entire prostate, mapping genetic alterations onto histological sections. In contrast to previous studies, researchers used spatial transcriptomics, meaning that researchers did not have to destroy the structure of the organ. This allowed them to analyse both the genetics and spatial landscape of the tissue together. This approach has not only allowed them to create this high-resolution map but has also revealed new insights into early events in cancer evolution.  

A new spatial transcriptomics approach

Acquired somatic mutations that cause cancer are usually hard to spot; unlike inherited mutations, they are only present in a small fraction of cells. In order to identify these mutations, previous studies took the approach of micro-dissecting organs to bulk sequence cancer tissue. This method has an inherent bias, as the regions are defined by histology or biomarkers.

However, this study leveraged new advances in spatial transcriptomics and therefore was not confined by these boundaries, so could instead perform organ-wide analysis. Furthermore, taking this approach means that the organ is not dissected and the structure of the organ remains intact, allowing them to precisely map genetic mutations on top of histological features.

Figure 1 ¦ a) Schematic illustrating how researchers conducted an organ-wide assessment of the prostate, creating “spots” to match up mutation profiles to histological regions. b) Shows the histology status for each organ-wide section that underwent spatial transcriptomic analysis

Creating the map

In this way, researchers could create a map (see below) by matching mutational profiles of certain “spots” to the same histological “spot” on the organ. This spot-by-spot analysis means that researchers can compare benign and malignant tissue, identify border regions and map-out changes in clonal architecture in tumours and co-existing benign tissue. These “spots” represent 10 cells each, which is extremely high resolution; allowing researchers to zoom in from visible tissue, down to microscopic multi-cellular structures, into the specific genomes of cells, all without losing the overall landscape of the organ.

Figure 2 ¦ a) Phylogenetic tree of all the tumour clones identified from genome-wide analysis. b) Histology status of each “spot” on the prostate. c) Spatial map of the tumour clones of each “spot” on the prostate.

Findings and future directions

The results of this study revealed several surprising findings. Firstly, researchers discovered that genetic mutations associated with cancer were actually identified in healthy benign tissues. Furthermore, they found very high genetic variability within the tissue, which was something they weren’t expecting. Further investigations into other organs also supported these results, raising questions about the timing of genetic changes in early cancer evolution. Moreover, this presence of multiple “sub-clones” within an area of tissue also suggests there may be more differences in the mutational profile of low-grade versus high-grade tumours than was previously thought.

Further investigations could better help delineate clonal patterns within tumours and benign tissue and help develop a comprehensive model for how mutations arise and lead to cancer. By helping define the genetic events that take place in the transition from benign to malignant tissue, this study has significant implications for current methods of cancer prognostics and diagnostics.