Epigenetic Alterations in Pancreatic Cancer

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

Cancers ◽

10.3390/cancers13246354 ◽

2021 ◽

Vol 13 (24) ◽

pp. 6354

Author(s):

Inês Faleiro ◽

Vânia Palma Roberto ◽

Secil Demirkol Canli ◽

Nicolas A. Fraunhoffer ◽

Juan Iovanna ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Methylation ◽

Methylation Status ◽

Therapeutic Targets ◽

The Cancer Genome Atlas ◽

Prognostic Indicators ◽

Diagnostic Tools ◽

Akt Pathway ◽

Epigenetic Alterations ◽

Epigenetic Biomarkers

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.

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Coming in the Air: Hypoxia Meets Epigenetics in Pancreatic Cancer

Cells ◽

10.3390/cells9112353 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2353

Author(s):

Claudia Geismann ◽

Alexander Arlt

Keyword(s):

Pancreatic Cancer ◽

Immune Escape ◽

Treatment Options ◽

Tumor Development ◽

Therapy Resistance ◽

Ductal Adenocarcinoma ◽

Epigenetic Alterations ◽

Hypoxic Conditions ◽

The Us ◽

Desmoplastic Stroma

With a five-year survival rate under 9%, pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest tumors. Although the treatment options are slightly improving, PDAC is the second leading cause of cancer related death in 2020 in the US. In addition to a pronounced desmoplastic stroma reaction, pancreatic cancer is characterized by one of the lowest levels of oxygen availability within the tumor mass and these hypoxic conditions are known to contribute to tumor development and progression. In this context, the major hypoxia associated transcription factor family, HIF, regulates hundreds of genes involved in angiogenesis, metabolism, migration, invasion, immune escape and therapy resistance. Current research implications show, that hypoxia also modulates diverse areas of epigenetic mechanisms like non-coding RNAs, histone modifications or DNA methylation, which cooperate with the hypoxia-induced transcription factors as well as directly regulate the hypoxic response pathways. In this review, we will focus on hypoxia-mediated epigenetic alterations and their impact on pancreatic cancer.

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The role of epigenetic alterations in pancreatic cancer

Journal of Hepato-Biliary-Pancreatic Surgery ◽

10.1007/s00534-005-1057-1 ◽

2006 ◽

Vol 13 (4) ◽

pp. 286-295 ◽

Cited By ~ 59

Author(s):

Norihiro Sato ◽

Michael Goggins

Keyword(s):

Pancreatic Cancer ◽

Epigenetic Alterations

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Alteration of Epigenetic Modifiers in Pancreatic Cancer and Its Clinical Implication

Journal of Clinical Medicine ◽

10.3390/jcm8060903 ◽

2019 ◽

Vol 8 (6) ◽

pp. 903 ◽

Cited By ~ 5

Author(s):

Yu-Hsuan Hung ◽

Ming-Chuan Hsu ◽

Li-Tzong Chen ◽

Wen-Chun Hung ◽

Mei-Ren Pan

Keyword(s):

Pancreatic Cancer ◽

Clinical Symptoms ◽

Abdominal Cavity ◽

Risk Groups ◽

Epigenetic Alterations ◽

Synthetic Lethal ◽

The Past ◽

Epigenetic Modifiers ◽

Molecular Aspects ◽

Pancreatic Cancer Therapy

The incidence of pancreatic cancer has considerably increased in the past decade. Pancreatic cancer has the worst prognosis among the cancers of the digestive tract because the pancreas is located in the posterior abdominal cavity, and most patients do not show clinical symptoms for early detection. Approximately 55% of all patients are diagnosed with pancreatic cancer only after the tumors metastasize. Therefore, identifying useful biomarkers for early diagnosis and screening high-risk groups are important to improve pancreatic cancer therapy. Recent emerging evidence has suggested that genetic and epigenetic alterations play a crucial role in the molecular aspects of pancreatic tumorigenesis. Here, we summarize recent progress in our understanding of the epigenetic alterations in pancreatic cancer and propose potential synthetic lethal strategies to target these genetic defects to treat this deadly disease.

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