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Circulating nucleosomes as epigenetic biomarkers in pancreatic cancer.

Bauden M, Pamart D, Ansari D, Herzog M, Eccleston M, Micallef J, Andersson B, Andersson R - Clin Epigenetics (2015)

Bottom Line: Nucleosomes are the repeating subunits of DNA and histone proteins that constitute human chromatin.The study comprised serum samples from 59 individuals, including 25 patients with resectable pancreatic cancer, 10 patients with benign pancreatic disease, and 24 healthy individuals using Nucleosomics(®), a novel ELISA method.Combining CA 19-9 with a panel of four cfnucleosome biomarkers gave an AUC of 0.98 with an overall sensitivity of 92 % at 90 % specificity.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Clinical Sciences, Lund, Lund University and Skåne University Hospital, Lund, SE-221 85 Lund, Sweden.

ABSTRACT

Background: To improve the prognosis of patients with pancreatic cancer, new biomarkers are required for earlier, pre-symptomatic diagnosis. Epigenetic mutations take place at the earliest stages of tumorigenesis and therefore offer new approaches for detecting and diagnosing disease. Nucleosomes are the repeating subunits of DNA and histone proteins that constitute human chromatin. Because of their release into the circulation, intact nucleosome levels in serum or plasma can serve as diagnostic disease biomarkers, and elevated levels have been reported in various cancers. However, quantifying nucleosomes in the circulation for cancer detection has been challenging due to nonspecific elevation in sera of patients with benign diseases. Here, we report for the first time differential, disease-associated epigenetic profiles of intact cell-free nucleosomes (cfnucleosomes) containing specific DNA and histone modifications as well as histone variants circulating in the blood. The study comprised serum samples from 59 individuals, including 25 patients with resectable pancreatic cancer, 10 patients with benign pancreatic disease, and 24 healthy individuals using Nucleosomics(®), a novel ELISA method.

Results: Multivariate analysis defined a panel of five serum cfnucleosome biomarkers that gave an area under the curve (AUC) of 0.95 for the discrimination of pancreatic cancer from healthy controls, which was superior to the diagnostic performance of the common pancreatic tumor biomarker, carbohydrate antigen 19-9 (CA 19-9) with an AUC of 0.87. Combining CA 19-9 with a panel of four cfnucleosome biomarkers gave an AUC of 0.98 with an overall sensitivity of 92 % at 90 % specificity.

Conclusions: The present study suggests that global epigenetic profiling of cfnucleosomes in serum using a simple NuQ(®) immunoassay-based approach can provide novel diagnostic biomarkers in pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus

Discrimination of four NuQ® assay panel combined with CA 19-9 for pancreatic cancer, benign disease, and healthy controls. Improved separation between the pancreatic cancer (n = 25), the benign samples (n = 10), and healthy controls (n = 24) was achieved with pre-processed ELISA data from four nucleosomal biomarkers combined with CA 19-9. A linear model (Fisher’s linear discriminant) was used to generate a weighted sum of values assigned as arbitrary units (AU) = −0.788 (5MC) − 2.338 (H2AZ) + 1.959 (H2A1.1) + 0.672 (H3K4Me2) + 0.782 (CA 19-9). P value was determined by the Mann-Whitney U test. Box plots indicate the median and 25th and 75th percentiles. Whiskers indicate the 5th and 95th percentiles
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Fig3: Discrimination of four NuQ® assay panel combined with CA 19-9 for pancreatic cancer, benign disease, and healthy controls. Improved separation between the pancreatic cancer (n = 25), the benign samples (n = 10), and healthy controls (n = 24) was achieved with pre-processed ELISA data from four nucleosomal biomarkers combined with CA 19-9. A linear model (Fisher’s linear discriminant) was used to generate a weighted sum of values assigned as arbitrary units (AU) = −0.788 (5MC) − 2.338 (H2AZ) + 1.959 (H2A1.1) + 0.672 (H3K4Me2) + 0.782 (CA 19-9). P value was determined by the Mann-Whitney U test. Box plots indicate the median and 25th and 75th percentiles. Whiskers indicate the 5th and 95th percentiles

Mentions: A box plot derived from the optimal panel of five assays (model 1) is shown in Fig. 1. The AUC for discrimination of cancer vs. healthy and benign was 0.92, which exceeded that of CA 19-9 with an AUC of 0.84 in our cohort (Fig. 2). A box plot for a similar model (model 2), in which the lowest weighted assay (nucleosome-associated H3K119Ub) in model 1 was replaced with CA 19-9, is shown in Fig. 3. The AUC for discrimination of cancer vs. healthy and benign groups increased to 0.94 (Fig. 2). For discrimination of cancer vs. healthy groups, the five cfnucleosome biomarker panel (model 1) had an AUC of 0.95 compared to 0.87 for CA 19-9. The four cfnucleosome plus CA 19-9 biomarker panel (model 2) increased the AUC to 0.98 (Fig. 4).Fig. 1


Circulating nucleosomes as epigenetic biomarkers in pancreatic cancer.

Bauden M, Pamart D, Ansari D, Herzog M, Eccleston M, Micallef J, Andersson B, Andersson R - Clin Epigenetics (2015)

Discrimination of four NuQ® assay panel combined with CA 19-9 for pancreatic cancer, benign disease, and healthy controls. Improved separation between the pancreatic cancer (n = 25), the benign samples (n = 10), and healthy controls (n = 24) was achieved with pre-processed ELISA data from four nucleosomal biomarkers combined with CA 19-9. A linear model (Fisher’s linear discriminant) was used to generate a weighted sum of values assigned as arbitrary units (AU) = −0.788 (5MC) − 2.338 (H2AZ) + 1.959 (H2A1.1) + 0.672 (H3K4Me2) + 0.782 (CA 19-9). P value was determined by the Mann-Whitney U test. Box plots indicate the median and 25th and 75th percentiles. Whiskers indicate the 5th and 95th percentiles
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4597435&req=5

Fig3: Discrimination of four NuQ® assay panel combined with CA 19-9 for pancreatic cancer, benign disease, and healthy controls. Improved separation between the pancreatic cancer (n = 25), the benign samples (n = 10), and healthy controls (n = 24) was achieved with pre-processed ELISA data from four nucleosomal biomarkers combined with CA 19-9. A linear model (Fisher’s linear discriminant) was used to generate a weighted sum of values assigned as arbitrary units (AU) = −0.788 (5MC) − 2.338 (H2AZ) + 1.959 (H2A1.1) + 0.672 (H3K4Me2) + 0.782 (CA 19-9). P value was determined by the Mann-Whitney U test. Box plots indicate the median and 25th and 75th percentiles. Whiskers indicate the 5th and 95th percentiles
Mentions: A box plot derived from the optimal panel of five assays (model 1) is shown in Fig. 1. The AUC for discrimination of cancer vs. healthy and benign was 0.92, which exceeded that of CA 19-9 with an AUC of 0.84 in our cohort (Fig. 2). A box plot for a similar model (model 2), in which the lowest weighted assay (nucleosome-associated H3K119Ub) in model 1 was replaced with CA 19-9, is shown in Fig. 3. The AUC for discrimination of cancer vs. healthy and benign groups increased to 0.94 (Fig. 2). For discrimination of cancer vs. healthy groups, the five cfnucleosome biomarker panel (model 1) had an AUC of 0.95 compared to 0.87 for CA 19-9. The four cfnucleosome plus CA 19-9 biomarker panel (model 2) increased the AUC to 0.98 (Fig. 4).Fig. 1

Bottom Line: Nucleosomes are the repeating subunits of DNA and histone proteins that constitute human chromatin.The study comprised serum samples from 59 individuals, including 25 patients with resectable pancreatic cancer, 10 patients with benign pancreatic disease, and 24 healthy individuals using Nucleosomics(®), a novel ELISA method.Combining CA 19-9 with a panel of four cfnucleosome biomarkers gave an AUC of 0.98 with an overall sensitivity of 92 % at 90 % specificity.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Clinical Sciences, Lund, Lund University and Skåne University Hospital, Lund, SE-221 85 Lund, Sweden.

ABSTRACT

Background: To improve the prognosis of patients with pancreatic cancer, new biomarkers are required for earlier, pre-symptomatic diagnosis. Epigenetic mutations take place at the earliest stages of tumorigenesis and therefore offer new approaches for detecting and diagnosing disease. Nucleosomes are the repeating subunits of DNA and histone proteins that constitute human chromatin. Because of their release into the circulation, intact nucleosome levels in serum or plasma can serve as diagnostic disease biomarkers, and elevated levels have been reported in various cancers. However, quantifying nucleosomes in the circulation for cancer detection has been challenging due to nonspecific elevation in sera of patients with benign diseases. Here, we report for the first time differential, disease-associated epigenetic profiles of intact cell-free nucleosomes (cfnucleosomes) containing specific DNA and histone modifications as well as histone variants circulating in the blood. The study comprised serum samples from 59 individuals, including 25 patients with resectable pancreatic cancer, 10 patients with benign pancreatic disease, and 24 healthy individuals using Nucleosomics(®), a novel ELISA method.

Results: Multivariate analysis defined a panel of five serum cfnucleosome biomarkers that gave an area under the curve (AUC) of 0.95 for the discrimination of pancreatic cancer from healthy controls, which was superior to the diagnostic performance of the common pancreatic tumor biomarker, carbohydrate antigen 19-9 (CA 19-9) with an AUC of 0.87. Combining CA 19-9 with a panel of four cfnucleosome biomarkers gave an AUC of 0.98 with an overall sensitivity of 92 % at 90 % specificity.

Conclusions: The present study suggests that global epigenetic profiling of cfnucleosomes in serum using a simple NuQ(®) immunoassay-based approach can provide novel diagnostic biomarkers in pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus