Differential methylation landscape of pancreatic ductal adenocarcinoma and its precancerous lesions

Bararia, Akash; Dey, Santu; Gulati, Sumit; Ghatak, Soumya; Ghosh, Saswata; Banerjee, Sudeep; Sikdar, Nilabja

doi:10.1016/j.hbpd.2020.03.010

Cited by 23 publications

(19 citation statements)

References 90 publications

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“…Cumulative genetic and epigenetic events seem to contribute to this transformation and further differentiate specific cancer types and subtypes. While the genetic landscape of PCA has been known for years [ 8 , 9 , 10 , 11 , 12 , 13 ], recent efforts have contributed to characterising the epigenetic one [ 14 , 15 , 16 , 17 , 18 ]. The most important genetic events in pancreatic ductal adenocarcinoma (PDAC), the most common type of PCA, are the activation of the oncogene KRAS and the inactivation of the tumour suppressor genes cyclin dependent kinase inhibitor 2A (CDKN2A), tumour protein p53 (TP53), and SMAD4 [ 8 , 9 , 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…Epigenetic regulation comprises dynamic events that impact on gene expression and play a major role in the heterogeneity of PCA [ 14 , 17 , 18 , 33 ]. In agreement, epigenetic regulation is implicated in the normal development and function of the pancreas and deregulation of these mechanisms can result in the development of pancreatic diseases including PCA [ 18 , 23 , 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

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

Faleiro

Roberto

Canli

et al. 2021

Cancers

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Faleiro

Roberto

Canli

et al. 2021

Cancers

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“…Along with genetic alterations, studies in the past decade showed that epigenetic alterations contribute to PDAC development and pathogenesis (Mazor et al, 2016, Mishra and Guda, 2017; Gregório et al, 2020). Studies also showed that precancerous lesions of PDAC harbour DNA methylation alterations in the known epigenetic driver genes (Bararia et al, 2020). Unusual gene expression is not always due to change in coding sequence but is also related to irregular CpG island methylation profile developed in the DNA’s regulatory region (Hervouet et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Past studies had shown that both genetic and epigenetic alterations contributed to PDAC initiation and progression (Biankin et al, 2012; Lomberk et al, 2019; Bararia et al, 2020). PDAC diagnosis based on gene-mutation has only brought partial success in early diagnosis and overall patients’ survival improvement (Lomberk et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Globally few studies have been done on investigating the changing epigenetic landscapes through progressive stages of PDAC(Nones et al, 2014; Mishra and Guda, 2017; Bararia et al, 2020). In this study, we have reported the altered genome-wide DNA methylation profile of PDAC across progressive stages and compared our results with the TCGA cohort.…”

Section: Introductionmentioning

confidence: 99%

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Altered DNA methylation in ion transport and immune signalling genes is associated with severity in Pancreatic Ductal Adenocarcinoma

Chatterjee

Bararia

et al. 2021

Preprint

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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading cancers worldwide and has a poor survival, with a relative five-year survival rate of only 8.5%. In this study we investigated epigenetic marks associated with PDAC severity and prognosis, through studying alterations in DNA methylation patterns. Methods: DNA methylome for tumor and adjacent normal tissue samples from PDAC patients (n=7) were generated using Illumina 450K bead chips. Differentially methylated positions (DMPs) were identified with |delta beta| > 0.2 and p-value<0.01 by comparing tumors with the adjacent normal tissues. Validation of differential methylation and associated gene expression at selected genes was carried out in an independent cohort PDAC patient. Results: We identified 76 DMPs in PDAC patients that mapped to 43 genes. Among them, 44.7% (n=34) were hypo-methylated and 55.3% (n=42) were hyper-methylated DMPs in cancer samples. The trends of change in methylation at these 76 DMPs from well to moderate were like that from moderate to poorly differentiated cancer samples. The gradual trend in differential methylation was observed both in our cohort and the TCGA-PAAD cohort, suggesting methylation marks can serve as early indicators of disease pathology. Altered promoter methylation, which may affect gene expression, was observed for transcription regulators (BHLHE23, GSC2, FOXE1 and TWIST1), gated ion channels (KCNA6, and CACNB2), tumor suppressors (RASSF1, SPRED2, and NPY) and genes functioning in interferon signalling (SIGIRR, MX2, and OAS2). We also have compared the TCGA-PAAD dataset with normal pancreatic tissue data from GTEx V8 dataset leading to a confluent observation. Conclusions: We reported the first study on methylome in PDAC tumors from patients in India. We identified altered DNA methylation associated with increasing severity in PDAC among some genes like SIGIRR, MX2 along with other previously reported loci. We also concluded a confluence in our observation when comparing the TCGA-PAAD dataset with GTEx V8 dataset.

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Potential association between PSCA rs2976395 functional variant and pancreatic cancer risk

Corradi,

Lencioni,

Felici

et al. 2024

Intl Journal of Cancer

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Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single‐nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV‐SNPs and 133,615 CoRSIV‐mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10−5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan‐meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association.

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Differential methylation landscape of pancreatic ductal adenocarcinoma and its precancerous lesions

Cited by 23 publications

References 90 publications

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

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

Altered DNA methylation in ion transport and immune signalling genes is associated with severity in Pancreatic Ductal Adenocarcinoma

Potential association between PSCA rs2976395 functional variant and pancreatic cancer risk

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