A new study identified key changes in gene expression and tissue composition in premalignant tumours, providing potential targets for prevention, diagnosis and treatment. Published in Nature Genetics, the study charted the cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC).
Researchers from Stanford University of Medicine generated single-cell chromatin accessibility profiles and single-cell transcriptomes from patients with or without germline APC mutations. The work was conducted as part of the Human Tumour Atlas Network.
The identification of genes and pathways that drive the development of invasive cancers has been widely studied in large-scale genomics efforts. However, most studies have focused on the bulk profiling of advanced stage tumours and have largely ignored pre-malignant lesions.
“Strategies to identify individuals in a premalignant stage, where interventions might be highly efficacious, promise tractable means to prevent cancer deaths,” the authors noted.
Colorectal cancers follow a nearly universal progression from normal to atypical to carcinoma, making them ideal to study.
For example, an estimated 80–90% of colorectal tumours are initiated by loss of APC, subsequently leading to intestinal hyperplasia.
Exhausted T cells, stem-like phenotypes and an influenced tumour microenvironment
The researchers used single-nucleus RNA sequencing (snRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq). They profiled single-nuclei transcriptomes and epigenomes from 1,000 to 10,000 cells per sample of healthy colon, polyps and CRCs.
The study found large shifts in fibroblast subpopulations that occurred along the transition from normal colon to CRC and a subpopulation of exhausted T cells that were present only in CRC tissue. They also observed a much larger fraction of cells exhibited a stem-like state (both transcriptionally and epigenetically) within polyps and CRCs.
In addition, they found compositional and cell state changes of noncancerous cells, including fibroblasts and immune cells, which may have influenced the tumour microenvironment to drive cancer progression.
The researchers also demonstrated that accessibility changes in polyps strongly anti-correlated with DNA methylation changes in sporadic CRC. A subset of these regions changed their accessibility state early in the malignant continuum. This suggests potential strategies for detection of premalignant polyps.
A new strategy for premalignant polyps
Currently, clinical guidelines for the timing and frequency of follow-up endoscopic screening after polypectomy depends on the size and degree of dysplasia of the polyps removed. The authors found variability in the degree of transformation in polyps with the same dysplasia classification. This work presents a strategy to order premalignant polyps by their degree of malignancy. This may be useful for staging polyps and assessing clinical risk.
The authors wrote, “Our single-cell atlas of colon cancer tumorigenesis fills [a knowledge] gap by identifying key changes in chromatin accessibility, gene expression and tissue composition that occur along this transformation, and provides a wealth of potential targets for prevention, diagnosis and treatment of malignancy.”
Written by Poppy Jayne Morgan, Front Line Genomics
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