CpG island methylator phenotype in adenocarcinomas from the digestive tract: Methods, conclusions, and controversies

Sánchez-Vega, Francisco; Gotea, Valer; Chen, Yunching; Elnitski, Laura

doi:10.4251/wjgo.v9.i3.105

Cited by 9 publications

(7 citation statements)

References 98 publications

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“…The existence of tumors characterized by simultaneous hypermethylation of a large number of CpG islands was described in colorectal cancer and called the CpG island methylator phenotype [3]. This molecular phenotype occurs in 15–20% of malignant colorectal tumors [101]. Development of CIMP-positive tumors is associated with elderly age, female gender, higher degree of differentiation and mucinous histological type, localization in the proximal colon, mutations in KRAS or BRAF , and wild-type TP53 [25, 102].…”

Section: Discussionmentioning

confidence: 99%

The CIMP-high phenotype is associated with energy metabolism alterations in colon adenocarcinoma

et al. 2019

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Background CpG island methylator phenotype (CIMP) is found in 15–20% of malignant colorectal tumors and is characterized by strong CpG hypermethylation over the genome. The molecular mechanisms of this phenomenon are not still fully understood. The development of CIMP is followed by global gene expression alterations and metabolic changes. In particular, CIMP-low colon adenocarcinoma (COAD), predominantly corresponded to consensus molecular subtype 3 (CMS3, “Metabolic”) subgroup according to COAD molecular classification, is associated with elevated expression of genes participating in metabolic pathways. Methods We performed bioinformatics analysis of RNA-Seq data from The Cancer Genome Atlas (TCGA) project for CIMP-high and non-CIMP COAD samples with DESeq2, clusterProfiler, and topGO R packages. Obtained results were validated on a set of fourteen COAD samples with matched morphologically normal tissues using quantitative PCR (qPCR). Results Upregulation of multiple genes involved in glycolysis and related processes ( ENO2, PFKP, HK3, PKM, ENO1, HK2, PGAM1, GAPDH, ALDOA, GPI, TPI1, and HK1 ) was revealed in CIMP-high tumors compared to non-CIMP ones. Most remarkably, the expression of the PKLR gene, encoding for pyruvate kinase participating in gluconeogenesis, was decreased approximately 20-fold. Up to 8-fold decrease in the expression of OGDHL gene involved in tricarboxylic acid (TCA) cycle was observed in CIMP-high tumors. Using qPCR, we confirmed the increase (4-fold) in the ENO2 expression and decrease (2-fold) in the OGDHL mRNA level on a set of COAD samples. Conclusions We demonstrated the association between CIMP-high status and the energy metabolism changes at the transcriptomic level in colorectal adenocarcinoma against the background of immune pathway activation. Differential methylation of at least nine CpG sites in OGDHL promoter region as well as decreased OGDHL mRNA level can potentially serve as an additional biomarker of the CIMP-high status in COAD. Electronic supplementary material The online version of this article (10.1186/s12881-019-0771-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The CIMP-high phenotype is associated with energy metabolism alterations in colon adenocarcinoma

et al. 2019

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“…Wnt inhibitory factor 1 (WIF1) is a tumor suppressor, which interacts with Wnt protein to inhibit the canonical and non-canonical Wnt pathways. It has been reported that silencing of WIF1 via methylation is associated with cancers, such as colon cancer (6). A previous study additionally reported that WIF1 inhibited the Wnt signaling pathway by inhibiting β-catenin accumulation, suppressed esophageal cancer and decreased the expression of E2F transcription factor 1, cyclin D1 and c-Myc proto-oncogene protein (c-Myc) to promote the apoptosis of hepatoma cells (7).…”

Section: Introductionmentioning

confidence: 98%

Genistein inhibits invasion and migration of colon cancer cells by recovering WIF1 expression

2018

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Colon cancer is characterized by invasion and migration. DNA methylation of CpG islands in tumor suppressor genes is considered to be an epigenetic mechanism underlying cancer development. Epigenetic silencing of a gene may be reversed by drugs, including genistein. The present study aimed to determine the effect of genistein on Wnt inhibitory factor 1 (WIF1) and invasion, and migration of colon cancer cells. The viability of HT29 colon cancer cells was suppressed by genistein in a dose dependent manner. Following 72 h of treatment with 10, 20 and 60 µmol/l genistein, increased demethylation of WIF1 was induced in a dose‑dependent manner. Additionally, the invasive/migratory abilities of cells treated with genistein decreased in a dose‑dependent manner. Reverse transcription‑quantitative polymerase chain reaction and western blot analyses were performed to identify the mRNA and protein expression levels of invasion/migration‑associated factors. Following treatment with genistein, matrix metalloproteinase (MMP) 2 and MMP9 expression levels decreased, whereas the expression of metalloproteinase inhibitor 1 and E‑cadherin increased significantly. In addition, the expression levels of proto‑oncogene Wnt‑1 (Wnt‑1)/β‑catenin pathway‑associated factors, β‑catenin, c‑Myc proto‑oncogene protein and cyclin D1 decreased in a dose‑dependent manner following treatment with genistein. The invasive/migratory abilities of cells transfected with WIF1‑small interfering (si) RNA, and those transfected with WIF1‑siRNA and treated with genistein, increased notably compared with the control group. The present study demonstrated that genistein was able to inhibit the cell invasion and migration of colon cancer cells by inducing demethylation, and recovering the activity of WIF1 by altering the expression of invasion‑associated factors, and components of the Wnt signaling pathway.

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“…Cancer-associated CpG island promotor hypermethylation patterns are determined by the tissue of origin [13]. The methylome analysis of our case showed the highest similarity to upper gastrointestinal adenocarcinoma [14]. However, a gastrointestinal primary was never detected.…”

Section: Discussionmentioning

confidence: 85%

A Rare Case of Breast Malignancy in an Adolescent Woman: Lessons Learned from Diagnosis and Management

et al. 2020

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Introduction: Primary breast malignancy in adolescent women is very rare and differs in several aspects from findings in adult women. Case Presentation: A young woman aged 16 years presented with a locally aggressive breast tumor. The patient received cisplatin-based chemotherapy followed by tumor resection assuming a diagnosis of germ cell tumor. Four months later, she developed locally recurrent disease and underwent a mastectomy. No definite diagnosis was agreed upon despite intensive pathological workup. Subsequent management consisted of follow-up only and the patient remains in complete remission 9 years later. Conclusion: This case demonstrates the difficulty of diagnosis and management of rare malignancies in adolescents, and highlights the importance of international and interdisciplinary collaboration in diagnosis and clinical decision-making.

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CpG island methylator phenotype in adenocarcinomas from the digestive tract: Methods, conclusions, and controversies

Cited by 9 publications

References 98 publications

The CIMP-high phenotype is associated with energy metabolism alterations in colon adenocarcinoma

The CIMP-high phenotype is associated with energy metabolism alterations in colon adenocarcinoma

Genistein inhibits invasion and migration of colon cancer cells by recovering WIF1 expression

A Rare Case of Breast Malignancy in an Adolescent Woman: Lessons Learned from Diagnosis and Management

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