Methylation of Tumor Suppressor Genes in Autoimmune Pancreatitis

Kinugawa, Yasuhiro; Uehara, Takeshi; Sakai, Kenji; Matsuda, Kazuyuki; Maruyama, Yasuhiro; Kobayashi, Yukihiro; Nakajima, Takahito; Hamano, Hideaki; Kawa, Shigeyuki; Higuchi, Kayoko; Hosaka, Noriko; Shiozawa, Satoshi; Ishigame, Hiroki; Ota, Hiroyoshi

doi:10.1097/mpa.0000000000000804

Cited by 18 publications

(16 citation statements)

References 30 publications

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“…CpG island methylation in promoters is frequently associated with gene silencing during tumorigenesis, providing an alternative mechanism to mutations by which tumor suppressor genes may be inactivated within a cancer cell [ 17 , 18 ]. In our exploratory cohort, as well as in other studies, the Tumor Suppressor Genes (TSGs) NPTX2 (Neuronal Pentraxin 2), CDO1 (Cysteine Dioxygenase Type 1), TFPI2 (Tissue Factor Pathway Inhibitor 2), SFRP1 (Secreted Frizzled Related Protein 1), SFRP2 (Secreted Frizzled Related Protein 2), PENK (Proenkephalin) and FOXE1 (Forkhead box E1) had a remarkable hypermethylation pattern in the PDAC group [ 19 , 20 , 21 , 22 , 23 , 24 ].…”

Section: Discussionsupporting

confidence: 63%

Calcium Signaling Alterations Caused by Epigenetic Mechanisms in Pancreatic Cancer: From Early Markers to Prognostic Impact

Gregório

Soares-Lima

Alemar

et al. 2020

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality rates. PDAC initiation and progression are promoted by genetic and epigenetic dysregulation. Here, we aimed to characterize the PDAC DNA methylome in search of novel altered pathways associated with tumor development. We examined the genome-wide DNA methylation profile of PDAC in an exploratory cohort including the comparative analyses of tumoral and non-tumoral pancreatic tissues (PT). Pathway enrichment analysis was used to choose differentially methylated (DM) CpGs with potential biological relevance. Additional samples were used in a validation cohort. DNA methylation impact on gene expression and its association with overall survival (OS) was investigated from PDAC TCGA (The Cancer Genome Atlas) data. Pathway analysis revealed DM genes in the calcium signaling pathway that is linked to the key pathways in pancreatic carcinogenesis. DNA methylation was frequently correlated with expression, and a subgroup of calcium signaling genes was associated with OS, reinforcing its probable phenotypic effect. Cluster analysis of PT samples revealed that some of the methylation alterations observed in the Calcium signaling pathway seemed to occur early in the carcinogenesis process, a finding that may open new insights about PDAC tumor biology.

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Section: Discussionsupporting

confidence: 63%

Calcium Signaling Alterations Caused by Epigenetic Mechanisms in Pancreatic Cancer: From Early Markers to Prognostic Impact

Gregório

Soares-Lima

Alemar

et al. 2020

Cancers

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“…Missense splice region variants of MEN1 and PKHD1 have been identified in patients with type 2 AIP [ 35 ]. In addition, methylation abnormality of tumor suppressor genes has also been reported in patients with AIP [ 36 ]. In the contrast no mutations of LAT gene in patients with IgG4-RD have so far been identified.…”

Section: Discussionmentioning

confidence: 99%

LatY136F knock-in mouse model for human IgG4-related disease

et al. 2018

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BackgroundThe adaptor protein Linker for activation of T cell (LAT) is a key signaling hub used by the T cell antigen receptor. Mutant mice expressing loss-of-function mutations affecting LAT and including a mutation in which tyrosine 136 is replaced by a phenylalanine (LatY136F) develop lymphoproliferative disorder involving T helper type 2 effector cells capable of triggering a massive polyclonal B cell activation that leads to hypergammaglobulinemia G1 and E and to non-resolving inflammation and autoimmunity. The purpose of this study was to evaluate whether the phenotypes of LatY136F knock-in mice resemble the immunohistopathological features of immunoglobulin G4-related disease (IgG4-RD).MethodsLatY136F knock-in mice were sacrificed at 4–20 weeks of age, and pancreas, kidney, salivary gland and lung were obtained. All organs were stained with hematoxylin-eosin and with Azan for estimation of collagen in fibrosis, and the severity scores of inflammation and fibrosis were evaluated. Immunostainings were performed to analyze the types of infiltrating cells. In addition, the effects of corticosteroid treatment on the development of tissue lesions and serum levels of IgG1 were assessed.ResultsTissue lesions characterized by inflammatory mononuclear cell infiltration and fibrosis were detected in pancreas, kidney, and salivary gland starting from 6 weeks of age. Immunostainings showed pronounced infiltration of plasma cells, CD4-positive T cells, and macrophages. Infiltrating plasma cells predominantly expressed IgG1. The extent of inflammation in pancreas and salivary glands was markedly reduced by corticosteroid treatment.ConclusionsLatY136F knock-in mice displayed increased production of Th2-type IgG1 (a homologue of human IgG4) and developed multiple organ tissue lesions reminiscent of those seen in patients with IgG4-RD. Moreover, the development of these tissue lesions was highly sensitive to corticosteroid treatment like in IgG4-RD. For these reasons we consider the LatY136F knock-in mouse strain to represent a promising model for human IgG4-RD.

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“…Conversely, no KRAS mutation at known tumor-promoting sites has so far been observed in AIP [47]. Finally, the mutation of the STK11 , a known risk factor for PTs, has recently been described in CP [17].…”

Section: The Molecular Landscape Of Pancreatic Cancer and Pancreatitismentioning

confidence: 99%

“…BRCA1 , APC , CDKN2A , and TIMP3 were methylated in 60%, 59%, 39%, and 31% of the PT cases, respectively [57]. Finally, the DNA methylation levels of six genes frequently hypermethylated in PT ( CCND2 , CDKN2A , FOXE1 , NPTX2 , PENK , TFPI2 ) were analyzed in AIP specimens [47], showing no significant hypermethylation in both AIP or healthy pancreas.…”

Section: Differentially Dna-methylated Genes In Pancreatic Tumor and mentioning

confidence: 99%

Deciphering DNA methylation signatures of pancreatic cancer and pancreatitis

et al. 2019

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Background Chronic pancreatitis presents a high risk of inflammation-related progression to pancreatic cancer. Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The high mortality rate is directly related to the difficulty in promptly diagnosing the disease, which often presents as overt and advanced. Hence, early diagnosis for pancreatic cancer becomes crucial, propelling research into the molecular and epigenetic landscape of the disease. Main body Recent studies have shown that cell-free DNA methylation profiles from inflammatory diseases or cancer can vary, thus opening a new venue for the development of biomarkers for early diagnosis. In particular, cell-free DNA methylation could be employed in the identification of pre-neoplastic signatures in individuals with suspected pancreatic conditions, representing a specific and non-invasive method of early diagnosis of pancreatic cancer. In this review, we describe the molecular determinants of pancreatic cancer and how these are related to chronic pancreatitis. We will then present an overview of differential methylated genes in the two conditions, highlighting their diagnostic or prognostic potential. Conclusion Exploiting the relation between abnormally methylated cell-free DNA and pre-neoplastic lesions or chronic pancreatitis may become a game-changing approach for the development of tools for the early diagnosis of pancreatic cancer. Electronic supplementary material The online version of this article (10.1186/s13148-019-0728-8) contains supplementary material, which is available to authorized users.

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Methylation of Tumor Suppressor Genes in Autoimmune Pancreatitis

Abstract: These are the first studies characterizing methylation abnormalities in AIP. AIP's inflammatory condition may be related to carcinogenesis. Further study will elucidate methylation abnormalities associated with carcinogenesis in AIP.

Cited by 18 publications

References 30 publications

Calcium Signaling Alterations Caused by Epigenetic Mechanisms in Pancreatic Cancer: From Early Markers to Prognostic Impact

Calcium Signaling Alterations Caused by Epigenetic Mechanisms in Pancreatic Cancer: From Early Markers to Prognostic Impact

LatY136F knock-in mouse model for human IgG4-related disease

Deciphering DNA methylation signatures of pancreatic cancer and pancreatitis

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