Pan-cancer nucleosome landscapes reveal tumor heterogeneity and inform cell-free DNA-based detection

Background: The arrangement and presence of nucleosomes, the basic units of chromatin structure, are crucial for organizing DNA in human cells. However, how these patterns differ across various types of cancer and their potential to aid in non-invasive cancer diagnosis has not been thoroughly investigated. To address this gap, researchers conducted a comprehensive study of nucleosome organization in 410 primary tumors belonging to 23 different cancer types using a technique called ATAC-seq.

This data was then cross-referenced with independent MNase-seq results to ensure accuracy. The study aimed to identify common and cancer-specific nucleosome patterns, explore their connection to tumor diversity and regulatory changes, and assess the feasibility of using tissue-derived nucleosome signatures for cancer classification and detection using a type of DNA found in the bloodstream called circulating cell-free DNA (cfDNA).

The researchers discovered both shared and cancer-specific nucleosomes linked to distinct regulatory processes. Surprisingly, nucleosome occupancy provided additional insights compared to chromatin accessibility for categorizing tumors and uncovering molecular heterogeneity within individual cancers. This includes subgroups that are characteristic of Basal-like breast cancer.

In the case of hepatocellular carcinoma, analyzing differential nucleosome patterns revealed cancer-related changes in chromatin remodeling, involving key regulatory pathways, transcription factor motifs, and candidate genes. Crucially, the team found that nucleosome signatures derived from tissue could be detected in cfDNA, enabling the classification of tumors from three different cancer types with high accuracy (AUROC scores of 0.877, 0.930, and 0.773 in different cohorts).

Furthermore, the researchers created OncoNucAtlas, an open-access database that allows researchers to explore these nucleosome landscapes.

In conclusion, this study sheds light on the significance of cancer-associated nucleosome organization as a complementary source of epigenomic information. The findings also suggest that tissue-derived nucleosome signatures hold promise for the development of cfDNA-based cancer detection methods. The pan-cancer atlas generated in this study serves as a valuable resource for investigating tumor heterogeneity and advancing non-invasive cancer detection approaches.