Dataset Information

Targeted deep sequencing of plasma circulating cell-free DNA reveals Vimentin and Fibulin 1 as potential epigenetic biomarkers for hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, but is still lacking sensitive and specific biomarkers for early diagnosis and prognosis. In this study, we applied targeted massively parallel semiconductor sequencing to assess methylation on a panel of genes (FBLN1, HINT2, LAMC1, LTBP1, LTBP2, PSMA2, PSMA7, PXDN, TGFB1, UBE2L3, VIM and YWHAZ) in plasma circulating cell-free DNA (cfDNA) and to evaluate the potential of these genes as HCC biomarkers in two different series, one from France (42 HCC cases and 42 controls) and one from Thailand (42 HCC cases, 26 chronic liver disease cases and 42 controls). We also analyzed a set of HCC and adjacent tissues and liver cell lines to further compare with 'The Cancer Genome Atlas' (TCGA) data. The methylation in cfDNA was detected for FBLN1, PSMA7, PXDN and VIM, with differences in methylation patterns between cases and controls for FBLN1 and VIM. The average methylation level across analyzed CpG-sites was associated with higher odds of HCC for VIM (1.48 [1.02, 2.16] for French cases and 2.18 [1.28, 3.72] for Thai cases), and lower odds of HCC for FBLN1 (0.89 [0.76, 1.03] for French cases and 0.75 [0.63, 0.88] for Thai cases). In conclusion, our study provides evidence that changes in VIM and FBLN1 methylation levels in cfDNA are associated with HCC and could represent useful plasma-based biomarkers. Also, the potential to investigate methylation patterns in cfDNA could bring new strategies for HCC detection and monitoring high-risk groups and response to treatment.

SUBMITTER: Holmila R

PROVIDER: S-EPMC5363871 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Targeted deep sequencing of plasma circulating cell-free DNA reveals Vimentin and Fibulin 1 as potential epigenetic biomarkers for hepatocellular carcinoma.

Holmila Reetta R Sklias Athena A Muller David C DC Degli Esposti Davide D Guilloreau Paule P Mckay James J Sangrajrang Suleeporn S Srivatanakul Petcharin P Hainaut Pierre P Merle Philippe P Herceg Zdenko Z Nogueira da Costa Andre A

PloS one 20170323 3

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, but is still lacking sensitive and specific biomarkers for early diagnosis and prognosis. In this study, we applied targeted massively parallel semiconductor sequencing to assess methylation on a panel of genes (FBLN1, HINT2, LAMC1, LTBP1, LTBP2, PSMA2, PSMA7, PXDN, TGFB1, UBE2L3, VIM and YWHAZ) in plasma circulating cell-free DNA (cfDNA) and to evaluate the potential of these genes as HCC biomarkers in two ...[more]

PMID: 28333958

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Project description:BackgroundPatients with cirrhosis are at high risk of hepatocellular carcinoma (HCC). The SEPT9 gene is a key regulator of cell division and tumor suppressor whose hypermethylation is associated with liver carcinogenesis. The primary aim of this study was to evaluate the diagnostic accuracy of a PCR-based assay for the analysis of SEPT9 promoter methylation in circulating cell-free DNA (mSEPT9) for diagnosing HCC among cirrhotic patients.MethodsWe report two phase II biomarker studies that included cirrhotic patients with or without HCC from France (initial study) and Germany (replication study). All patients received clinical and biological evaluations, and liver imaging according to current recommendations. The primary outcome was defined as the presence of HCC according to guidelines from the American Association for the Study of Liver Diseases. The diagnosis of HCC was confirmed by abdominal contrast-enhanced computed tomography scan and systematically discussed in a multidisciplinary consultation meeting. HCC-free cirrhotic patients were recruited if the screening abdominal ultrasound showed no evidence of HCC at the time of blood sampling for the mSEPT9 test and on the next visit six months later. The adjudicating physicians were blinded to patient results associated with the mSEPT9 test.FindingsWe included 289 patients with cirrhosis (initial: 186; replication: 103), among whom 98 had HCC (initial: 51; replication: 47). The mSEPT9 test exhibited high diagnostic accuracy for HCC diagnosis, with an area under the receiver operating characteristic curve (AUROC) of 0.944 (0.900-0.970, p<0.0001) in the initial study (replication: 0.930 [0.862-0.971, p<0.0001]; meta-analysis: AUROC=0.940 [0.910-0.970, p<0.0001], no heterogeneity: I2=0%, p=0.67; and no publication bias). In multivariate logistic regression analysis, the number of positive mSEPT9 triplicates was the only independent variable significantly associated with HCC diagnosis (initial: OR=6.30, for each mSEPT9 positive triplicate [2.92-13.61, p<0.0001]; replication: OR=6.07 [3.25-11.35, p<0.0001]; meta-analysis: OR=6.15 [2.93-9.38, p<0.0001], no heterogeneity: I2=0%, p=0.95; no publication bias). AUROC associated with the discrimination of the logistic regression models in initial and validation studies were 0.969 (0.930-0.989) and 0.942 (0.878-0.978), respectively, with a pooled AUROC of 0.962 ([0.937-0.987, p<0.0001], no heterogeneity: I2=0%, p=0.36; and no publication bias).InterpretationAmong patients with cirrhosis, the mSEPT9 test constitutes a promising circulating epigenetic biomarker for HCC diagnosis at the individual patient level. Future prospective studies should assess the mSEPT9 test in the screening algorithm for cirrhotic patients to improve risk prediction and personalized therapeutic management of HCC.

Dataset Information

Targeted deep sequencing of plasma circulating cell-free DNA reveals Vimentin and Fibulin 1 as potential epigenetic biomarkers for hepatocellular carcinoma.

Publications

Targeted deep sequencing of plasma circulating cell-free DNA reveals Vimentin and Fibulin 1 as potential epigenetic biomarkers for hepatocellular carcinoma.

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