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Pan-Cancer Study Points to Epigenetic Contributors to Cancer Development, Metastasis

Molecular Generic

NEW YORK – A team led by researchers at Washington University has unearthed epigenomic drivers for cancer development and progression, including epigenetic alterations linked to previously described genetic contributors.

"This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions," co-senior and co-corresponding author Li Ding, a researcher affiliated with Washington University and its McDonnell Genome Institute and Siteman Cancer Center, and her colleagues wrote in Nature on Wednesday.

"Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression, and metastasis," the authors explained. "Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood."

Using a combination of single-cell RNA sequencing, single-nucleus RNA-seq, and single-nucleus ATAC-seq-based chromatin accessibility profiling, the researchers assessed transcriptomic and epigenetic features in more than 1 million individual cells per platform for up to 225 pan-cancer tumor samples spanning 11 cancer types.

With these data, along with clues from cells in 15 normal adjacent tissues, the team characterized epigenetic drivers behind cancer development and progression, from transcription factor motifs or regulons to chromatin accessibility patterns and cancer cell-specific differentially accessible chromatin regions.

"Advancing beyond previous bulk ATAC/RNA-seq studies," the authors explained, "our analysis provides nuanced insights into cancer biology, including cancer-specific epigenetic architecture, relationships between normal and malignant cells, and primary-to-metastatic transitions in the same lineage."

While cancer initiation was linked to epigenetic changes affecting pathways involved in TNF signaling, hypoxia, and TP53 activity, the team linked metastatic cancer transitions to alterations affecting estrogen response, apical cell junctions, and the process of epithelial-to-mesenchymal transition (EMT).

The investigators also flagged cancer transition-related regulatory regions within and across cancer types. While alterations affecting the PBX3 motif or regulatory regions influencing FGF19, ASAP2, and EN1 gene activity showed ties to specific cancer types, for example, they saw pan-cancer effects for epigenetic changes falling in GATA6 or FOX-family regulon motifs and regulatory regions influencing the ABCC1 and VEGFA genes.

"This study highlights the potential of [transcription factors] as prognostic markers, offering a deeper understanding of the molecular underpinnings driving cancer evolution," the authors reported, noting that the findings also highlighted that "correlations between epigenetic changes and genetic mutations within the same pathway are present across cancer types, suggesting numerous instances of cooperation in cancer transition programs."

Beyond the insights into the epigenomic and transcriptomic features found in cancer cells and the unaffected cells neighboring them, the team noted that the analyses provided a potential look at the regulatory programs that may serve as possible treatment targets down the road.

"Understanding the landscape of chromatin architecture across tumors, chromatin accessibility changes at critical cancer transitions, and the interplay between chromatin accessibility, genetic alterations, and transcriptional patterns is crucial to advancing cancer biology and clinical practice," the authors wrote, adding that "[c]ertain changes in chromatin accessibility that represent critical events/drivers of cancer initiation and metastatic spread may be potential therapeutic targets."