Research

Jump to: Review

21 pages, 14354 KiB

Open AccessArticle

DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study

by Inês Faleiro, Vânia Palma Roberto, Secil Demirkol Canli, Nicolas A. Fraunhoffer, Juan Iovanna, Ali Osmay Gure, Wolfgang Link and Pedro Castelo-Branco

Cancers 2021, 13(24), 6354; https://doi.org/10.3390/cancers13246354 - 17 Dec 2021

Cited by 5 | Viewed by 2913

Abstract

Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play [...] Read more.

Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets. Full article

(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)

► Show Figures

Figure 1

14 pages, 2036 KiB

Open AccessArticle

Genomic Instability of Circulating Tumor DNA as a Prognostic Marker for Pancreatic Cancer Survival: A Prospective Cohort Study

by Sang Myung Woo, Min Kyeong Kim, Boram Park, Eun-Hae Cho, Tae-Rim Lee, Chang-Seok Ki, Kyong-Ah Yoon, Yun-Hee Kim, Wonyoung Choi, Do Yei Kim, Jin-Hyeok Hwang, Jae Hee Cho, Sung-Sik Han, Woo Jin Lee, Sang-Jae Park and Sun-Young Kong

Cancers 2021, 13(21), 5466; https://doi.org/10.3390/cancers13215466 - 30 Oct 2021

Cited by 7 | Viewed by 2117

Abstract

Genomic instability of circulating tumor DNA (ctDNA) as a prognostic biomarker has not been evaluated in pancreatic cancer. We investigated the role of the genomic instability index of ctDNA in pancreatic ductal adenocarcinoma (PDAC). We prospectively enrolled 315 patients newly diagnosed with resectable [...] Read more.

Genomic instability of circulating tumor DNA (ctDNA) as a prognostic biomarker has not been evaluated in pancreatic cancer. We investigated the role of the genomic instability index of ctDNA in pancreatic ductal adenocarcinoma (PDAC). We prospectively enrolled 315 patients newly diagnosed with resectable (n = 110), locally advanced (n = 78), and metastatic (n = 127) PDAC from March 2015 through January 2020. Low-depth whole-genome cell-free DNA sequencing identified genome-wide copy number alterations using instability score (I-score) to reflect genome-wide instability. Plasma cell-free and matched tumor tissue DNA from 15 patients with resectable pancreatic cancer was sequenced to assess the concordance of chromosomal copy number alteration profiles. Associations of I-score with clinical factors or survival were assessed. Seventy-six patients had high genomic instability with I-score > 7.3 in pre-treatment ctDNA; proportions of high I-score were 5.5%, 5.1%, and 52% in resectable, locally advanced, and metastatic stages, respectively. Correlation coefficients between Z-scores of plasma and tissue DNA at segment resolution were high (r² = 0.82). Univariable analysis showed the association of I-score with progression-free survival in each stage. Multivariable analyses demonstrated that clinical stage-adjusted I-scores were significant factors for progression-free and overall survival. In these patients, ctDNA genomic I-scores provided prognostic information relevant to progression-free survival in each clinical stage. Full article

(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)

► Show Figures

Figure 1

13 pages, 2140 KiB

Open AccessArticle

Added Value of Tomoelastography for Characterization of Pancreatic Neuroendocrine Tumor Aggressiveness Based on Stiffness

by Emin Gültekin, Christoph Wetz, Jürgen Braun, Dominik Geisel, Christian Furth, Bernd Hamm, Ingolf Sack and Stephan R. Marticorena Garcia

Cancers 2021, 13(20), 5185; https://doi.org/10.3390/cancers13205185 - 15 Oct 2021

Cited by 9 | Viewed by 1796

Abstract

Purpose: To evaluate the diagnostic performance of tomoelastography in differentiating pancreatic neuroendocrine tumors (PNETs) from healthy pancreatic tissue and to assess the prediction of tumor aggressiveness by correlating PNET stiffness with PET derived asphericity. Methods: 13 patients with PNET were prospectively compared to [...] Read more.

Purpose: To evaluate the diagnostic performance of tomoelastography in differentiating pancreatic neuroendocrine tumors (PNETs) from healthy pancreatic tissue and to assess the prediction of tumor aggressiveness by correlating PNET stiffness with PET derived asphericity. Methods: 13 patients with PNET were prospectively compared to 13 age-/sex-matched heathy volunteers (CTR). Multifrequency MR elastography was combined with tomoelastography-postprocessing to provide high-resolution maps of shear wave speed (SWS in m/s). SWS of pancreatic neuroendocrine tumor (PNET-T) were compared with nontumorous pancreatic tissue in patients with PNET (PNET-NT) and heathy pancreatic tissue (CTR). The diagnostic performance of tomoelastography was evaluated by ROC-AUC analysis. PNET-SWS correlations were calculated with Pearson’s r. Results: SWS was higher in PNET-T (2.02 ± 0.61 m/s) compared to PNET-NT (1.31 ± 0.18 m/s, p < 0.01) and CTR (1.26 ± 0.09 m/s, p < 0.01). An SWS-cutoff of 1.46 m/s distinguished PNET-T from PNET-NT (AUC = 0.89; sensitivity = 0.85; specificity = 0.92) and a cutoff of 1.49 m/s differentiated pancreatic tissue of CTR from PNET-T (AUC = 0.96; sensitivity = 0.92; specificity = 1.00). The SWS of PNET-T was positively correlated with PET derived asphericity (r = 0.81; p = 0.01). Conclusions: Tomoelastography provides quantitative imaging markers for the detection of PNET and the prediction of greater tumor aggressiveness by increased stiffness. Full article

(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)

► Show Figures

Figure 1

17 pages, 311 KiB

Open AccessArticle

Associations between Nutritional and Immune Status and Clinicopathologic Factors in Patients with Pancreatic Cancer: A Comprehensive Analysis

by Beata Jabłońska, Krzysztof Pawlicki and Sławomir Mrowiec

Cancers 2021, 13(20), 5041; https://doi.org/10.3390/cancers13205041 - 09 Oct 2021

Cited by 15 | Viewed by 1796

Abstract

The aim of this study was to assess and analyze the nutritional status (NS) and immune status of pancreatic cancer (PC) patients. The retrospective analysis included 80 PC patients undergoing curative pancreatic resection in the Department of Digestive Tract Surgery of the Medical [...] Read more.

The aim of this study was to assess and analyze the nutritional status (NS) and immune status of pancreatic cancer (PC) patients. The retrospective analysis included 80 PC patients undergoing curative pancreatic resection in the Department of Digestive Tract Surgery of the Medical University (Katowice, Poland). Patients were divided by the tumor location (proximal vs. distal), age (≤65 years vs. >65 years), Nutritional Risk Score 2002 (NRS 2002) (<3 vs. ≥3), prognostic nutritional index (PNI) (<45 vs. ≥45), and the presence of postoperative complications (no-complication vs. complication) as well as the use of neoadjuvant chemotherapy (no neoadjuvant chemotherapy vs. neoadjuvant chemotherapy) into two subgroups, which were compared. Significantly higher weight loss was related to the proximal tumor location (p = 0.0104). Significantly lower serum total protein (p = 0.0447), albumin (p = 0.0468), hemoglobin (p = 0.0265) levels, and PNI (p = 0.03) were reported in older patients. The higher nutritional risk according to NRS 2002 was significantly associated with higher age (p = 0.0187), higher weight loss (p < 0.01), lower body mass index (BMI) (p = 0.0293), lower total lymphocyte count (p = 0.0292), longer duration of hospitalization (p = 0.020), neoadjuvant chemotherapy (p < 0.01), and preoperative biliary drainage (p = 0.0492). The lower PNI was significantly associated with higher weight loss (p = 0.0407), lower serum total protein and albumin concentration, lymphocyte count (p < 0.01) and higher neutrophil/lymphocyte (NLR), monocyte/lymphocyte (MLR), platelet/lymphocyte (PLR) ratios, and duration of hospitalization (p < 0.01). In the multiple logistic regression analysis, BMI ≥ 30 kg/m² (OR: 8.62; 95% CI: 1.24–60.04; p = 0.029521) and NRS 2002 ≥ 3 (OR: 2.87; 95% CI: 0.88–9.33; p = 0.048818) predicted postoperative complications. In the multiple linear regression analysis, the higher NRS 2002 score was linked with the longer duration of hospitalization (b = 7.67948; p = 0.043816), and longer duration of postoperative hospitalization was associated with a higher complication rate (b = 0.273183; p = 0.003100). Nutritional impairment correlates with a systemic inflammatory response in PC patients. Obesity (BMI ≥ 30 kg/m²) and malnutrition (NRS 2002 ≥ 3) predict postoperative complications, which are associate with a longer hospital stay. Assessment of nutritional and immune status using basic diagnostic tools and PNI and immune ratio (NLR, MLR, PLR) calculation should be the standard management of PC patients before surgery to improve the postoperative outcome. Full article

(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)

16 pages, 3597 KiB

Open AccessArticle

Prediction of Early Distant Recurrence in Upfront Resectable Pancreatic Adenocarcinoma: A Multidisciplinary, Machine Learning-Based Approach

by Diego Palumbo, Martina Mori, Francesco Prato, Stefano Crippa, Giulio Belfiori, Michele Reni, Junaid Mushtaq, Francesca Aleotti, Giorgia Guazzarotti, Roberta Cao, Stephanie Steidler, Domenico Tamburrino, Emiliano Spezi, Antonella Del Vecchio, Stefano Cascinu, Massimo Falconi, Claudio Fiorino and Francesco De Cobelli

Cancers 2021, 13(19), 4938; https://doi.org/10.3390/cancers13194938 - 30 Sep 2021

Cited by 16 | Viewed by 1977

Abstract

Despite careful selection, the recurrence rate after upfront surgery for pancreatic adenocarcinoma can be very high. We aimed to construct and validate a model for the prediction of early distant recurrence (<12 months from index surgery) after upfront pancreaticoduodenectomy. After exclusions, 147 patients [...] Read more.

Despite careful selection, the recurrence rate after upfront surgery for pancreatic adenocarcinoma can be very high. We aimed to construct and validate a model for the prediction of early distant recurrence (<12 months from index surgery) after upfront pancreaticoduodenectomy. After exclusions, 147 patients were retrospectively enrolled. Preoperative clinical and radiological (CT-based) data were systematically evaluated; moreover, 182 radiomics features (RFs) were extracted. Most significant RFs were selected using minimum redundancy, robustness against delineation uncertainty and an original machine learning bootstrap-based method. Patients were split into training (n = 94) and validation cohort (n = 53). Multivariable Cox regression analysis was first applied on the training cohort; the resulting prognostic index was then tested in the validation cohort. Clinical (serum level of CA19.9), radiological (necrosis), and radiomic (SurfAreaToVolumeRatio) features were significantly associated with the early resurge of distant recurrence. The model combining these three variables performed well in the training cohort (p = 0.0015, HR = 3.58, 95%CI = 1.98–6.71) and was then confirmed in the validation cohort (p = 0.0178, HR = 5.06, 95%CI = 1.75–14.58). The comparison of survival curves between low and high-risk patients showed a p-value <0.0001. Our model may help to better define resectability status, thus providing an actual aid for pancreatic adenocarcinoma patients’ management (upfront surgery vs. neoadjuvant chemotherapy). Independent validations are warranted. Full article

(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)

► Show Figures

Figure 1

13 pages, 1140 KiB

Open AccessArticle

Predicting Survival in Patients with Pancreatic Cancer by Integrating Bone Marrow FDG Uptake and Radiomic Features of Primary Tumor in PET/CT

by Jeong Won Lee, Sang-Heum Park, Hyein Ahn, Sang Mi Lee and Su Jin Jang

Cancers 2021, 13(14), 3563; https://doi.org/10.3390/cancers13143563 - 16 Jul 2021

Cited by 14 | Viewed by 4428

Abstract

The purpose of this study was to evaluate the prognostic significance of FDG uptake of bone marrow (BM SUV) and to investigate its role combined with radiomic features of primary tumors in improving the prediction of overall survival (OS) in patients with pancreatic [...] Read more.

The purpose of this study was to evaluate the prognostic significance of FDG uptake of bone marrow (BM SUV) and to investigate its role combined with radiomic features of primary tumors in improving the prediction of overall survival (OS) in patients with pancreatic cancer. We retrospectively enrolled 65 pancreatic cancer patients with staging FDG PET/CT. BM SUV and conventional imaging parameters of primary tumors including total lesion glycolysis (TLG) were measured. First-order and higher-order textural features of primary cancer were extracted using PET textural analysis. Associations of PET/CT parameters of bone marrow (BM) and primary cancer with OS were assessed. BM SUV as well as TLG and first-order entropy of pancreatic cancer were significant independent predictors of OS in multivariable analysis. A PET/CT scoring system based on the cumulative scores of these three independent predictors enabled patient stratification into three distinct prognostic groups. The scoring system yielded a good prognostic stratification based on subgroup analysis irrespective of tumor stage and treatment modality. BM SUV was an independent predictor of OS in pancreatic cancer patients. The PET/CT scoring system that integrated PET/CT parameters of primary tumors and BM can provide prognostic information in pancreatic cancer independent of tumor stage and treatment. Full article

(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)

► Show Figures

Figure 1

17 pages, 2119 KiB

Open AccessArticle

Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features

by Jérôme Raffenne, Fernando A. Martin, Rémy Nicolle, Marina Konta, Yuna Blum, Jérôme Torrisani, Francesco Puleo, Jean Baptiste Bachet, Magali Svrcek, Armel Bardier-Dupas, Jean Francois Emile, Peter Demetter, Miroslav Radman, Jean Luc Van Laethem, Pascal Hammel, Vinciane Rebours, Valérie Paradis, Anne Couvelard and Jérôme Cros

Cancers 2021, 13(6), 1234; https://doi.org/10.3390/cancers13061234 - 11 Mar 2021

Cited by 9 | Viewed by 2098

Abstract

Pancreatic ducal adenocarcinoma is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years (y.o.). While the genomic and transcriptomic landscapes of late-onset tumors (LOT) have been described, little is known about early-onset tumors (EOT). Ageing is [...] Read more.

Pancreatic ducal adenocarcinoma is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years (y.o.). While the genomic and transcriptomic landscapes of late-onset tumors (LOT) have been described, little is known about early-onset tumors (EOT). Ageing is known to impact DNA methylation and proteome integrity through carbonylation-related oxidative damages. We therefore aimed to assess the global molecular features of EOT. We compared 176 EOT (≤55 y.o.) and 316 LOT (≥70 y.o.) from three distinct surgical cohorts at the clinical/genomic/epigenomic/transcriptomic level. Furthermore, we assessed oxidative stress responses and oxidative proteome damages using 2D gel electrophoresis followed by mass spectrometry protein identification. There was no consistent clinical difference between EOT and LOT across the three cohorts. The mutational landscape of key driver genes and the global methylation profile were similar in the two groups. LOT did display age-related features such as enriched DNA repair gene signatures and upregulation of oxidative stress defenses together with increased proteome carbonylation. However, these age-related differences were more preeminent in non-tumor tissues while tumor proteome and proteome damages were fairly comparable. In conclusion, this multi-omics comparison showed that EOT harbor a comparable molecular profile to that of LOT. Full article

(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)

► Show Figures

Figure 1

11 pages, 1233 KiB

Open AccessArticle

Excision Repair Cross-Complementation Group 6 Gene Polymorphism Is Associated with the Response to FOLFIRINOX Chemotherapy in Asian Patients with Pancreatic Cancer

by Young Hoon Choi, Younggyun Lim, Ji Kon Ryu, Woo Hyun Paik, Sang Hyub Lee, Yong-Tae Kim and Ju Han Kim

Cancers 2021, 13(6), 1196; https://doi.org/10.3390/cancers13061196 - 10 Mar 2021

Viewed by 1960

Abstract

FOLFIRINOX is currently one of the standard chemotherapy regimens for pancreatic cancer patients, but little is known about the factors that can predict a response to it. We performed a study to discover novel DNA damage repair (DDR) gene variants associated with the [...] Read more.

FOLFIRINOX is currently one of the standard chemotherapy regimens for pancreatic cancer patients, but little is known about the factors that can predict a response to it. We performed a study to discover novel DNA damage repair (DDR) gene variants associated with the response to FOLFIRINOX chemotherapy in patients with pancreatic cancer. We queried a cohort of pancreatic cancer patients who received FOLFIRINOX chemotherapy as the first treatment and who had tissue obtained through an endoscopic ultrasound-guided biopsy that was suitable for DNA sequencing. We explored variants of 148 DDR genes based on whole exome sequencing and performed multivariate Cox regression to find genetic variants associated with progression-free survival (PFS). Overall, 103 patients were included. Among 2384 variants of 141 DDR genes, 612 non-synonymous variants of 123 genes were selected for Cox regression analysis. The multivariate Cox model showed that rs2228528 in ERCC6 was significantly associated with improved PFS (hazard ratio 0.54, p = 0.001). The median PFS was significantly longer in patients with rs2228528 genotype AA vs. genotype GA and GG (23.5 vs. 16.2 and 8.6 months; log-rank p < 0.001). This study suggests that rs2228528 in ERCC6 could be a potential predictor of response to FOLFIRINOX chemotherapy in patients with pancreatic cancer. Full article

(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)

► Show Figures

Figure 1

Review

Jump to: Research

26 pages, 3003 KiB

Open AccessReview

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

by Max M. Wattenberg and Kim A. Reiss

Cancers 2021, 13(18), 4716; https://doi.org/10.3390/cancers13184716 - 21 Sep 2021

Cited by 9 | Viewed by 2820

Abstract

Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique [...] Read more.

Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients. Full article

(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)

► Show Figures

Figure 1

14 pages, 2308 KiB

Open AccessReview

Divulging the Critical Role of HuR in Pancreatic Cancer as a Therapeutic Target and a Means to Overcome Chemoresistance

by Dimitrios Goutas, Nikolaos Goutas and Stamatios Theocharis

Cancers 2021, 13(18), 4634; https://doi.org/10.3390/cancers13184634 - 15 Sep 2021

Cited by 3 | Viewed by 2710

Abstract

Pancreatic cancer is set to become the most lethal and common type of cancer worldwide. This is partly attributed to the mutational burden that affects core signaling pathways and the crosstalk of tumor cells with their surrounding microenvironment, but it is also due [...] Read more.

Pancreatic cancer is set to become the most lethal and common type of cancer worldwide. This is partly attributed to the mutational burden that affects core signaling pathways and the crosstalk of tumor cells with their surrounding microenvironment, but it is also due to modern eating habits. Hyperadiposity along with the constant rise in metabolic syndrome’s incidence contribute to a state of metaflammation that impacts immune cells and causes them to shift towards an immunosuppressive phenotype that, ultimately, allows tumor cells to evade immune control. Unfortunately, among the conventional therapeutic modalities and the novel therapeutic agents introduced, pancreatic cancer still holds one of the lowest response rates to therapy. Human antigen R (HuR), an RNA binding protein (RBP), has been repeatedly found to be implicated in pancreatic carcinogenesis and chemotherapy resistance through the posttranscriptional binding and regulation of mRNA target genes. Additionally, its overexpression has been linked to adverse clinical outcomes, in terms of tumor grade, stage, lymph node status and metastasis. These properties suggest the prospective role that HuR’s therapeutic targeting can play in facilitating pancreatic neoplasia and could provide the means to overcome chemoresistance. Full article

(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Prognostic and Predictive Markers in Pancreatic Cancer

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI