Descripción del proyecto
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. But, 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. 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. In the first strategy, I will employ my previously developed synthetic histone modification readers to profile abundant histone modifications on cf-nucleosomes allowing me to seize up to 35 percent of the human genome non-invasively. I will prove this technology’s concept by detecting earlier stages of pancreatic cancer and simultaneously classifying molecular tumor subtypes. 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. In the second strategy, I will employ a computational pipeline to map cancer-specific bivalent sites across multiple cancer genomes. 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. 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.