Epigenomic determinants of the neuroendocrine phenotype as biomarkers for noninvasive diagnosis of neuroendocrine neoplasms

GEP-NENS are a heterogeneous group of diseases that encompasses relatively indolent and more aggressive tumors, sometimes with mixed exocrine/endocrine components (MINENS). Due to persistent uncertainties in diagnosis and treatment, prognosis of the mixed and more aggressive forms remains poor. Non-invasive tests would enable timely identification and monitoring over time. A better understanding of their biology and in particular of the phenotypic differentiation process may pave the way for novel therapies.
Key information can be obtained by studying the epigenetic landscape underlying cell differentiation
Among epigenetic markers, DNA methylation is particularly well suited for non-invasive detection as it can be measured in circulating tumor DNA (ctDNA). Additionally, DNA fragmentomics (ie the study of the particolar representation patterns along the genomic sequence in ctDNA) is a consequence of transcriotiona factor binding patterns and also can be used to infer cell of origin in ctDNA. New technologies like Oxford Nanopore Technologies (ONT) enable simultaneous analysis of DNA sequence and methylation. Previous studies identified distinct neuroendocrine epi-transcriptomic landscapes but were conducted on ¿bulk¿ tumor specimens, impeding the discrimination of signals specifically generated within neuroendocrine tumor cells from the noise due to surrounding nontumoral or exocrine tumoral cells.
Here, we will exploit epigenetic differences characterizing NE tumors to build a DNA methylation-based liquid biopsy assay able to detect circulating tumor DNA of NE derivation, to enable the non-invasive diagnosis and monitoring of GEP-NENS. This will be accompanied by the generation of high-throughput single cell multidimensional datasets to characterize the GEP- NENS epigenomes from primary surgical specimens. The test will be initially designed based on existing information and datasets generated on cell lines, refined based on the single cell data from primary human samples and finally validated in a prospective clinical validation study.