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Spatial Copy Number Variant Maps Shed Light on Clonal Cancer Development

NEW YORK – A team from the UK, Sweden, the US, and Finland has demonstrated that spatially profiling copy number patterns in normal and malignant organ sites can provide new insights into the clonal evolution of cancer. Specifically, the researchers drilled down on features found in the prostate.

"This high-resolution view impacts our way of addressing complex ecosystems such as cancer," co-senior and co-corresponding author Joakim Lundeberg, a researcher at the KTH Royal Institute of Technology in Sweden, said in a statement. "The possibility to identify early events is particularly exciting going forward."

As they reported in Nature on Wednesday, the researchers turned to a spatial transcriptomic strategy that combined tissue imaging with spatially barcoded copy number variant (CNV) and gene expression profiling to assess copy number clones in different parts of the prostate organ in cancerous or noncancerous states.

Using tens of thousands of areas in prostate tumor and nearby normal tissue from one individual, along with as many as 120,000 spatially defined tissue sample sites from 10 more individuals, the team explored phylogenetic relationships between the CNV-based clones, detecting clonal evolution clues that were fleshed out further with similar analyses on brain tumor, lymph node, ductal breast cancer, and squamous cell carcinoma skin samples.

"The tissue clone diversity over the five investigated tissue types was notably variable, with genomes ranging from homogenous to highly heterogeneous in both tumor and benign tissue," the authors noted, adding that "the spatial information allowed us to identify small clonal units not evident from morphology, which would therefore be overlooked by histologically guided laser microdissection or even random sampling of single cells."

In particular, the spatial sites profiled suggested that at least a subset of CNVs previously implicated in cancer also turns up in benign tissues from the same organ, the University of Oxford's Alastair Lamb, co-senior and co-corresponding author on the study, explained in a statement. He added that this result "has big implications for diagnosis and also potentially for deciding which bits of a cancer need treating."

With phylogenetic analyses, the team went on to retrace the evolution of cancer-related clones spanning benign to malignant tissue samples, narrowing in on copy number losses and gains that appeared to mark the ancestral clones that presaged the CNV clusters found in full-blown tumor samples.

"Defining the transition from benign to malignant tissue is fundamental to improving early diagnosis of cancer," the authors explained, noting that the current findings "suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution."