Dataset Information

Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA.

ABSTRACT: Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort (n?=?64) in comparison with a non-cancer cohort (n?=?243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function (GATA4, GATA6, PROX1, ONECUT1, MEIS2), and cancer pathogenesis (YAP1, TEAD1, PROX1, IGF1). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53. Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n?=?79) and 0.92-0.94 (two independent test sets, n?=?228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC?=?0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.

SUBMITTER: Guler GD

PROVIDER: S-EPMC7572413 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA.

Guler Gulfem D GD Ning Yuhong Y Ku Chin-Jen CJ Phillips Tierney T McCarthy Erin E Ellison Christopher K CK Bergamaschi Anna A Collin Francois F Lloyd Paul P Scott Aaron A Antoine Michael M Wang Wendy W Chau Kim K Ashworth Alan A Quake Stephen R SR Levy Samuel S

Nature communications 20201019 1

Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort (n = 64) in comparison with a non-cancer cohort (n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function (GATA4, GATA6, PROX1, ONECUT1, MEIS2), and ...[more]

PMID: 33077732

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Project description:Approximately 85% colorectal cancers (CRCs) are thought to evolve through the adenoma-to-carcinoma sequence associated with specific molecular alterations, including the 5-hydroxymethylcytosine (5hmC) signature in circulating cell-free DNA (cfDNA). To explore colorectal disease progression and evaluate the use of cfDNA as a potential diagnostic factor for CRC screening, here, we performed genome-wide 5hmC profiling in plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 plasma and 38 tissues), collected from 21 early-stage CRC patients, 21 AD patients, and 21 healthy controls (HC). The gDNA and cfDNA 5hmC signatures identified in gene bodies and promoter regions in CRC and AD groups were compared with those in HC group. All the differential 5hmC-modified regions (DhMRs) were gathered into four clusters: Disease-enriched, AD-enriched, Disease-lost, and AD-lost, with no overlap. AD-related clusters, AD-enriched and AD-lost, displayed the unique 5hmC signals in AD patients. Disease-enriched and Disease-lost clusters indicated the general 5hmC changes when colorectal lesions occurred. Cancer patients with a confirmable adenoma history segmentally gathered in AD-enriched clusters. KEGG functional enrichment and GO analyses determined distinct differential 5hmC-modified profiles in cfDNA of HC individuals, AD, and CRC patients. All patients had comprehensive 5hmC signatures where Disease-enriched and Disease-lost DhMR clusters demonstrated similar epigenetic modifications, while AD-enriched and AD-lost DhMR clusters indicated complicated subpopulations in adenoma. Analysis of CRC patients with adenoma history showed exclusive 5hmC-gain characteristics, consistent with the 'parallel' evolution hypothesis in adenoma, either developed through the adenoma-to-carcinoma sequence or not. These findings deepen our understanding of colorectal disease and suggest that the 5hmC modifications of different pathological subtypes (cancer patients with or without adenoma history) could be used to screen early-stage CRC and assess adenoma malignancy with large-scale follow-up studies in the future.

Dataset Information

Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA.

Publications

Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA.

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