Towards early cancer detection and tumor classification using epigenomic biomarkers in blood

Introduction

Early cancer detection could increase curative treatment and long-term survival. Dying cells release small DNA fragments wrapped around a core of histone proteins into the bloodstream, so-called circulating cell-free nucleosomes (cf-nucleosomes). They carry DNA sequence information and histone modifications stable in blood, reflecting promising epigenomic disease biomarkers.

Challenges in Detection

However, the low proportion of cf-nucleosomes originating from cancerous cells versus the large background of nucleosomes arising from dying blood cells poses significant challenges for early cancer detection using circulating cf-nucleosomes.

Proposed Strategies

In EpiCblood, I will tackle these challenges and propose two complementary strategies to increase the number of “cancer-signature” cf-nucleosomes for cancer detection and tumor classification.

Strategy 1: Synthetic Histone Modification Readers

1. I will employ my previously developed synthetic histone modification readers to profile abundant histone modifications on cf-nucleosomes.
2. This approach will allow me to seize up to 35 percent of the human genome non-invasively.
3. I will prove this technology’s concept by detecting earlier stages of pancreatic cancer and simultaneously classifying molecular tumor subtypes.

Strategy 2: Computational Mapping of Bivalent Sites

Furthermore, I hypothesize that tumorigenesis gives rise to cancer-specific genomic sites decorated with combinatorial histone marks, so-called “bivalent” regions, found explicitly in cancer and not in healthy adult cell types.

1. In the second strategy, I will employ a computational pipeline to map cancer-specific bivalent sites across multiple cancer genomes.
2. I will use my well-established combinatorial histone mark readers to test their diagnostic potential as cancer-specific biomarkers in blood plasma from healthy donors and cancer patients.

Conclusion

My genomics expertise and proven technology provide an excellent basis for accomplishing the planned goals. EpiCblood will be a major step towards developing precise and rich liquid biopsy assays for multiple clinical applications in cancer management.