The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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Guo, H., Vuille, J. A. et al. Cell 186(13), 2765-2782.E28 (2023).
doi: doi.org/10.1016/j.cell.2023.05.028.
Summary of the findings
Summary of the findingsIn addition to the established mechanism of silencing tumour suppressor genes through focal hypermethylation of CpG islands around gene promoters, long-range hypomethylation of gene-poor chromosomal regions (Partially Methylated Domains or PMDs) has been linked to silencing of resident protein-encoding genes. In their paper, Guo, Vuille, et al investigated DNA methylation features present in prostate cancer, with a focus on circulating tumour cells (CTCs). Using single-cell multiomics sequencing, combining single-cell whole-genome bisulfite sequencing with single-cell RNA-seq, the authors mapped the precise borders of PMDs that are shared across the diverse single CTCs from individual patients and across different patients. They identified 40 core PMDs, shared across all single prostate cancer cells, and traced their common origin to the early stages of tumorigenesis (Gleason stage 6) . Remarkably, a single locus encoding the entire family of CD1 genes implicated in lipid antigen presentation to NK-T cells is silenced early in tumorigenesis and restored gene expression reactivates immune cell tumour recognition. Large scale DNA hypomethylation is detectable using nanopore long-range native sequencing of CTC-enriched blood samples from patients with both localized and metastatic prostate cancer. Notably, while long range DNA hypomethylation during early tumorigenesis provides an epigenetic mechanism for bi-allelic silencing of some immune related genes, key proliferative genes that also reside within PMDs are spared, as they are surrounded by tightly demarcated islands with preserved DNA methylation.
Future impact
The specific immune-rich “CD1A-IFI16” genomic locus that is silenced by profound, early DNA hypomethylation is shared across 33 different cancer types, in addition to prostate cancer, pointing to a new, potentially targetable signaling pathway contributing to early immune surveillance of cancer. Measurements of long range DNA hypomethylation are feasible in CTC-enriched blood specimens and may enhance non-invasive detection of early malignancies.
