scholarly journals Immunoprofiles and DNA Methylation of Inflammatory Marker Genes in Ulcerative Colitis-Associated Colorectal Tumorigenesis

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1440
Author(s):  
Satu Mäki-Nevala ◽  
Sanjeevi Ukwattage ◽  
Erkki-Ville Wirta ◽  
Maarit Ahtiainen ◽  
Ari Ristimäki ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Immune Cell ◽  
Cpg Island ◽  
Inflammatory Marker ◽  
Normal Mucosa ◽  
Field Cancerization ◽  
Marker Genes ◽  
Cpg Island Methylator Phenotype ◽  
Repair Gene ◽  
Methylator Phenotype

Immunological and epigenetic changes are interconnected and contribute to tumorigenesis. We determined the immunoprofiles and promoter methylation of inflammation-related genes for colitis-associated colorectal carcinomas (CA-CRC). The results were compared with Lynch syndrome (LS)-associated colorectal tumors, which are characterized by an active immune environment through inherited mismatch repair defects. CA-CRCs (n = 31) were immunohistochemically evaluated for immune cell scores (ICSs) and PDCD1 and CD274 expression. Seven inflammation-associated genes (CD274, NTSR1, PPARG, PTGS2, PYCARD, SOCS1, and SOCS2), the repair gene MGMT, and eight standard marker genes for the CpG Island Methylator Phenotype (CIMP) were investigated for promoter methylation in CA-CRCs, LS tumors (n = 29), and paired normal mucosae by multiplex ligation-dependent probe amplification. All but one CA-CRCs were microsatellite-stable and all LS tumors were microsatellite-unstable. Most CA-CRCs had a high ICS (55%) and a positive CD274 expression in immune cells (52%). NTSR1 revealed frequent tumor-specific hypermethylation in CA-CRC and LS. When compared to LS mucosae, normal mucosae from patients with CA-CRC showed significantly higher methylation of NTSR1 and most CIMP markers. In conclusion, CA-CRCs share a frequent ICShigh/CD274pos expression pattern with LS tumors. Elevated methylation in normal mucosa may indicate field cancerization as a feature of CA-CRC-associated tumorigenesis.

scholarly journals IGFBP3 Promoter Methylation in Colorectal Cancer: Relationship with Microsatellite Instability, CpG Island Methylator Phenotype, p53

Neoplasia ◽  
2007 ◽  
Vol 9 (12) ◽  
pp. 1091-1098 ◽  
Author(s):  
Takako Kawasaki ◽  
Katsuhiko Nosho ◽  
Mutsuko Ohnishi ◽  
Yuko Suemoto ◽  
Gregory J. Kirkner ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Promoter Methylation ◽  
Cpg Island ◽  
Cpg Island Methylator Phenotype ◽  
Methylator Phenotype

scholarly journals CpG Island Methylator Phenotype and Prognosis of Colorectal Cancer in Northeast China

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Xia Li ◽  
Fulan Hu ◽  
Yibaina Wang ◽  
Xiaoping Yao ◽  
Zuoming Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Promoter Methylation ◽  
Northeast China ◽  
Proportional Hazards ◽  
Cpg Island ◽  
Sporadic Colorectal Cancer ◽  
Cpg Island Methylator Phenotype ◽  
Methylator Phenotype ◽  
Worse Prognosis

Purpose. To investigate the association between CpG island methylator phenotype (CIMP) and the overall survival of sporadic colorectal cancer (CRC) in Northeast China.Methods. 282 sporadic CRC patients were recruited in this study. We selectedMLH1,MGMT,p16,APC,MINT1,MINT31, andRUNX3as the CIMP panel markers. The promoter methylation was assessed by methylation sensitive high resolution melting (MS-HRM). Proportional hazards-regression models were fitted with computing hazard ratios (HR) and the corresponding 95% confidence intervals (95% CI).Results. 12.77% (36/282) of patients were CIMP-0, 74.1% (209/282) of patients were CIMP-L, and 13.12% (37/282) of patients were CIMP-H. The five-year survival of the 282 CRC patients was 58%. There was significant association betweenAPCgene promoter methylation and CRC overall survival (HR = 1.61; 95% CI: 1.05–2.46;P=0.03). CIMP-H was significantly associated with worse prognosis compared to CIMP-0 (HR = 3.06; 95% CI: 1.19–7.89;P=0.02) and CIMP-L (HR = 1.97; 95% CI: 1.11–3.48;P=0.02), respectively. While comparing with the combine of CIMP-L and CIMP-0 (CIMP-L/0), CIMP-H also presented a worse prognosis (HR = 2.31; 95% CI: 1.02–5.24;P=0.04).Conclusion. CIMP-H may be a predictor of a poor prognosis of CRC in Northeast China patients.

scholarly journals Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3529
Author(s):  
Sabine Meessen ◽  
Nicola Currey ◽  
Zeenat Jahan ◽  
Hannah W. Parker ◽  
Mark A. Jenkins ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Predictive Marker ◽  
Proximal Colon ◽  
Marker Genes ◽  
Colorectal Carcinomas ◽  
Loss Of Function ◽  
Cpg Island Methylator Phenotype ◽  
Tetranucleotide Repeat ◽  
Methylator Phenotype

MSH3 gene or protein deficiency or loss-of-function in colorectal cancer can cause a DNA mismatch repair defect known as “elevated microsatellite alterations at selected tetranucleotide repeats” (EMAST). A high percentage of MSI-H tumors exhibit EMAST, while MSI-L is also linked with EMAST. However, the distribution of CpG island methylator phenotype (CIMP) within the EMAST spectrum is not known. Five tetranucleotide repeat and five MSI markers were used to classify 100 sporadic colorectal tumours for EMAST, MSI-H and MSI-L according to the number of unstable markers detected. Promoter methylation was determined using methylation-specific PCR for MSH3, MCC, CDKN2A (p16) and five CIMP marker genes. EMAST was found in 55% of sporadic colorectal carcinomas. Carcinomas with only one positive marker (EMAST-1/5, 26%) were associated with advanced tumour stage, increased lymph node metastasis, MSI-L and lack of CIMP-H. EMAST-2/5 (16%) carcinomas displayed some methylation but MSI was rare. Carcinomas with ≥3 positive EMAST markers (13%) were more likely to have a proximal colon location and be MSI-H and CIMP-H. Our study suggests that EMAST/MSI-L is a valuable prognostic and predictive marker for colorectal carcinomas that do not display the high methylation phenotype CIMP-H.

scholarly journals Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation

2018 ◽  
Vol 55 (4) ◽  
pp. 240-248 ◽  
Author(s):  
Monika Morak ◽  
Ayseguel Ibisler ◽  
Gisela Keller ◽  
Ellen Jessen ◽  
Andreas Laner ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Promoter Methylation ◽  
Transcriptional Repression ◽  
De Novo ◽  
Cpg Island ◽  
Promoter Sequence ◽  
Cpg Island Methylator Phenotype ◽  
Allele Specific ◽  
Methylator Phenotype

BackgroundGermline defects in MLH1, MSH2, MSH6 and PMS2 predisposing for Lynch syndrome (LS) are mainly based on sequence changes, whereas a constitutional epimutation of MLH1(CEM) is exceptionally rare. This abnormal MLH1 promoter methylation is not hereditary when arising de novo, whereas a stably heritable and variant-induced CEM was described for one single allele. We searched for MLH1 promoter variants causing a germline or somatic methylation induction or transcriptional repression.MethodsWe analysed the MLH1 promoter sequence in five different patient groups with colorectal cancer (CRC) (n=480) composed of patients with i) CEM (n=16), ii) unsolved loss of MLH1 expression in CRC (n=37), iii) CpG-island methylator-phenotype CRC (n=102), iv) patients with LS (n=83) and v) MLH1-proficient CRC (n=242) as controls. 1150 patients with non-LS tumours also served as controls to correctly judge the results.ResultsWe detected 10 rare MLH1 promoter variants. One novel, complex MLH1 variant c.-63_-58delins18 is present in a patient with CRC with CEM and his sister, both showing a complete allele-specific promoter methylation and transcriptional silencing. The other nine promoter variants detected in 17 individuals were not associated with methylation. For four of these, a normal, biallelic MLH1 expression was found in the patients' cDNA.ConclusionWe report the second promoter variant stably inducing a hereditary CEM. Concerning the classification of promoter variants, we discuss contradictory results from the literature for two variants, describe classification discrepancies between existing rules for five variants, suggest the (re-)classification of five promoter variants to (likely) benign and regard four variants as functionally unclear.

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