IGF2 differentially methylated region hypomethylation in relation to pathological and molecular features of serrated lesions

AIM:To investigate insulin-like growth factor 2(IGF2)differentially methylated region(DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions.METHODS:To accurately analyze the association between the histological types and molecular features of...

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Published in:	World journal of gastroenterology : WJG 2014-08, Vol.20 (29), p.10050-10061
Main Authors:	Naito, Takafumi, Nosho, Katsuhiko, Ito, Miki, Igarashi, Hisayoshi, Mitsuhashi, Kei, Yoshii, Shinji, Aoki, Hironori, Nomura, Masafumi, Sukawa, Yasutaka, Yamamoto, Eiichiro, Adachi, Yasushi, Takahashi, Hiroaki, Hosokawa, Masao, Fujita, Masahiro, Takenouchi, Toshinao, Maruyama, Reo, Suzuki, Hiromu, Baba, Yoshifumi, Imai, Kohzoh, Yamamoto, Hiroyuki, Ogino, Shuji, Shinomura, Yasuhisa
Format:	Article
Language:	eng
Subjects:	Adaptor Proteins, Signal Transducing - genetics Adenoma - chemistry Adenoma - genetics Adenoma - mortality Adenoma - pathology Aged Biomarkers, Tumor - analysis Biomarkers, Tumor - genetics BRAF Chi-Square Distribution Class I Phosphatidylinositol 3-Kinases Colon Colorectal Colorectal Neoplasms - chemistry Colorectal Neoplasms - genetics Colorectal Neoplasms - mortality Colorectal Neoplasms - pathology Colorectum DNA Methylation DNA Modification Methylases - genetics DNA Repair Enzymes - genetics Female Gene Expression Regulation, Neoplastic Genetic Predisposition to Disease Humans Insulin-Like Growth Factor II - analysis Insulin-Like Growth Factor II - genetics Kaplan-Meier Estimate Logistic Models Long Interspersed Nucleotide Elements Male Microsatellite Instability Middle Aged Multivariate Analysis MutL Protein Homolog 1 neoplasia Nuclear Proteins - genetics Original Phenotype Phosphatidylinositol 3-Kinases - genetics polyp Prognosis Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins p21(ras) ras Proteins - genetics Tumor Suppressor Proteins - genetics
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Summary:	AIM:To investigate insulin-like growth factor 2(IGF2)differentially methylated region(DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions.METHODS:To accurately analyze the association between the histological types and molecular features of each type of serrated lesion,we consecutively collected1386 formalin-fixed paraffin-embedded tissue specimens that comprised all histological types[hyperplastic polyps(HPs,n=121),sessile serrated adenomas(SSAs,n=132),traditional serrated adenomas(TSAs,n=111),non-serrated adenomas(n=195),and colorectal cancers(n=827)].We evaluated the methylation levels of IGF2 DMR0 and long interspersed nucleotide element-1(LINE-1)in HPs(n=115),SSAs(n=120),SSAs with cytological dysplasia(n=10),TSAs(n=91),TSAs with high-grade dysplasia(HGD)(n=15),non-serrated adenomas(n=80),non-serrated adenomas with HGD(n=105),and CRCs(n=794).For the accurate quantification of the relative methylation levels(scale 0%-100%)of IGF2 DMR0 and LINE-1,we used bisulfite pyrosequencing method.Tumor specimens were analyzed for microsatellite instability,KRAS(codons 12 and 13),BRAF(V600E),and PIK3CA(exons 9and 20)mutations;MLH1 and MGMT methylation;and IGF2 expression by immunohistochemistry.RESULTS:The distribution of the IGF2 DMR0 methylation level in 351 serrated lesions and 185 non-serrated adenomas(with or without HGD)was as follows:mean61.7,median 62.5,SD 18.0,range 5.0-99.0,interquartile range 49.5-74.4.The IGF2 DMR0 methylation level was divided into quartiles(Q1≥74.5,Q2 62.6-74.4,Q3 49.6-62.5,Q4≤49.5)for further analysis.With regard to the histological type,the IGF2 DMR0 methylation levels of SSAs(mean±SD,73.1±12.3)were significantly higher than those of HPs(61.9±20.5),TSAs(61.6±19.6),and non-serrated adenomas(59.0±15.8)(P<0.0001).The IGF2 DMR0 methylation level was inversely correlated with the IGF2 expression level(r=-0.21,P=0.0051).IGF2 DMR0 hypomethylation was less frequently detected in SSAs compared with HPs,TSAs,and non-serrated adenomas(P<0.0001).Multivariate logistic regression analysis also showed that IGF2 DMR0 hypomethylation was inversely associated with SSAs(P<0.0001).The methylation levels of IGF2 DMR0 and LINE-1 in TSAs with HGD(50.2±18.7and 55.7±5.4,respectively)were significantly lower than those in TSAs(61.6±19.6 and 58.8±4.7,respectively)(IGF2 DMR0,P=0.038;LINE-1,P=0.024).CONCLUSION:IGF2 DMR0 hypomethylation may be an infrequent epigenetic alteration in the SSA pathwa
ISSN:	1007-9327 2219-2840