A Plasma-Derived Protein-Metabolite Multiplexed Panel for Early-Stage Pancreatic Cancer

Fahrmann, Johannes F.; Bantis, Leonidas E.; Capello, Michela; Scélo, Ghislaine; Dennison, Jennifer B.; Patel, Nikul; Murage, Eunice; Vykoukal, Jody; Kundnani, Deepali L.; Foretová, Lenka; Fabiánovà, Eleonóra; Holcátová, Ivana; Janout, Vladimí­r; Feng, Ziding; Yip-Schneider, Michele; Zhang, Jianjun; Brand, Randall E.; Taguchi, Ayumu; Maitra, Anirban; Brennan, Paul; Schmidt, C. Max; Hanash, Samir M.

doi:10.1093/jnci/djy126

Cited by 88 publications

(101 citation statements)

References 31 publications

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“…Little is known about HIST1H2BK in previous cancer studies. For certain markers identified here, their potential for non-invasive cancer diagnosis has been reported previously, such as serum TIMP1 and FGA proteins used for the diagnosis of PDAC and gastric cancer, respectively 36–38. Collectively, these results suggested that plasma EVs contain a considerable number of exLRs that are potential biomarkers for PDAC detection.…”

Section: Discussionsupporting

confidence: 74%

Plasma extracellular vesicle long RNA profiling identifies a diagnostic signature for the detection of pancreatic ductal adenocarcinoma

Yu¹,

Liao

et al. 2019

Gut

161

151

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ObjectivePancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose at resectable stage. Recent studies have suggested that extracellular vesicles (EVs) contain long RNAs. The aim of this study was to develop a diagnostic (d-)signature for the detection of PDAC based on EV long RNA (exLR) profiling.DesignWe conducted a case-control study with 501 participants, including 284 patients with PDAC, 100 patients with chronic pancreatitis (CP) and 117 healthy subjects. The exLR profile of plasma samples was analysed by exLR sequencing. The d-signature was identified using a support vector machine algorithm and a training cohort (n=188) and was validated using an internal validation cohort (n=135) and an external validation cohort (n=178).ResultsWe developed a d-signature that comprised eight exLRs, including FGA, KRT19, HIST1H2BK, ITIH2, MARCH2, CLDN1, MAL2 and TIMP1, for PDAC detection. The d-signature showed high accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.960, 0.950 and 0.936 in the training, internal validation and external validation cohort, respectively. The d-signature was able to identify resectable stage I/II cancer with an AUC of 0.949 in the combined three cohorts. In addition, the d-signature showed superior performance to carbohydrate antigen 19-9 in distinguishing PDAC from CP (AUC 0.931 vs 0.873, p=0.028).ConclusionThis study is the first to characterise the plasma exLR profile in PDAC and to report an exLR signature for the detection of pancreatic cancer. This signature may improve the prognosis of patients who would have otherwise missed the curative treatment window.

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Section: Discussionsupporting

confidence: 74%

Plasma extracellular vesicle long RNA profiling identifies a diagnostic signature for the detection of pancreatic ductal adenocarcinoma

Yu¹,

Liao

et al. 2019

Gut

161

151

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“…One study found a panel of six metabolites including 5-hydroxytryptophan can distinguish benign pancreatic diseases from early-stage cancer with high accuracy (34). Another study showed that a metabolite panel that includes decreased indole derivatives significantly increased the discriminating capacity of plasma protein biomarkers (35). In this study, we found that the serum levels of indole showed the largest reduction in cases in comparison with controls.…”

Section: Discussionsupporting

confidence: 50%

A Prospective Targeted Serum Metabolomics Study of Pancreatic Cancer in Postmenopausal Women

Jiao

Maity

Coarfa

et al. 2019

Cancer Prevention Research

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To examine the association between metabolic deregulation and pancreatic cancer, we conducted a two-stage case-control targeted metabolomics study using prediagnostic sera collected one year before diagnosis in the Women's Health Initiative study. We used the LC/MS to quantitate 470 metabolites in 30 matched case/control pairs. From 180 detectable metabolites, we selected 14 metabolites to be validated in additional 18 matched case/control pairs. We used the paired t test to compare the concentrations of each metabolite between cases and controls and used the log fold change (FC) to indicate the magnitude of difference. FDR adjusted q-value < 0.25 was indicated statistically significant. Logistic regression model and ROC curve analysis were used to evaluate the clinical utility of the metabolites. Among 30 case/control pairs, 1-methyl-L-tryptophan (L-1MT) was significantly lower in the cases than in the controls (log 2 FC ¼ À0.35; q-value ¼ 0.03). The area under the ROC curve was 0.83 in the discrimination analysis based on the levels of L-1MT, acadesine, and aspartic acid. None of the metabolites was validated in additional independent 18 case/control pairs. No significant association was found between the examined metabolites and undiagnosed pancreatic cancer.

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“…These genes included the previously described PDA growth-promoting genes, as well as the spermine/spermidine acetyltransferase SAT1 , and PP2A subunit B isoform δ ( PPP2R2D ). SAT1 modulates cell migration and resistance in multiple tumor types, while PPP2R2D is a component of the tumor suppressive phosphatase PP2A 61–66 . With the exception of PPP2R2D , which displayed significant 3’-UTR lengthening and downregulation in tumors, all of the validated genes were significantly shortened and overexpressed in the TCGA-PAAD dataset.…”

Section: Resultsmentioning

confidence: 99%

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

Venkat

Tisdale

Schwarz

et al. 2019

Preprint

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Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3’-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDAs). We report widespread, recurrent and functionally relevant 3’-UTR alterations associated with gene expression changes of known and newly identified PDA growth-promoting genes and experimentally validate the effects of these APA events on expression. We find enrichment for APA events in genes associated with known PDA pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3’-UTR forms of metabolic genes. Survival analyses reveal a subset of 3’-UTR alterations that independently characterize a poor prognostic cohort among PDA patients. Finally, we identify and validate the casein kinase CK1α as an APA-regulated therapeutic target in PDA. Knockdown or pharmacological inhibition of CK1α attenuates PDA cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of pro-tumorigenic gene expression in PDA via the loss of miRNA regulation.

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A Plasma-Derived Protein-Metabolite Multiplexed Panel for Early-Stage Pancreatic Cancer

Abstract: A metabolite panel in combination with CA19-9, TIMP1, and LRG1 exhibited substantially improved performance in the detection of early-stage PDAC compared with a protein panel alone.

Cited by 88 publications

References 31 publications

Plasma extracellular vesicle long RNA profiling identifies a diagnostic signature for the detection of pancreatic ductal adenocarcinoma

Plasma extracellular vesicle long RNA profiling identifies a diagnostic signature for the detection of pancreatic ductal adenocarcinoma

A Prospective Targeted Serum Metabolomics Study of Pancreatic Cancer in Postmenopausal Women

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

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