title: Genetic alterations in colorectal cancers with demethylation of insulin-like growth factor II.
abstract: Loss of genomic imprinting is an epigenetic alteration of some cancers involving the absence of parental origin-specific expression of imprinted genes. Loss of genomic imprinting of insulin-like growth factor II is often detected in colorectal cancer. However, the genetic alterations accompanied by colorectal cancer with insulin-like growth factor II loss of genomic imprinting have not been fully determined. Genomic DNA samples were collected from 52 colorectal cancer tissues and analyzed. The loss of insulin-like growth factor II genomic imprinting status was determined by assessing the demethylation of the insulin-like growth factor II differentially methylated region using bisulfite sequencing. The molecular signatures were also examined: genetic mutations of KRAS, BRAF, and PIK3CA; the expression of CTNNB1 and TP53; and microsatellite instability status. Several cases of colorectal cancer with normal insulin-like growth factor II imprinting were located in the distal colon; in contrast, colorectal cancer with loss of genomic imprinting tended to be found in the proximal colon (22.7 versus 56.6%). The PIK3CA gene mutation was highly detected in normal imprinting tumors compared to colorectal cancers with insulin-like growth factor II loss of genomic imprinting (27.3% versus 6.7%). In multivariate analysis of these clinicopathologic and molecular factors of tumors, statistically significant relationships were observed among the proximal location of the tumor (odds ratio, 12.9; 95% confidence interval, 1.52-110.13), PIK3CA genetic mutation (odds ratio, 0.082; 95% confidence interval, 0.01-0.73), and insulin-like growth factor II genomic imprinting status. Our findings indicate that colorectal cancers with demethylation of the insulin-like growth factor II gene are distinct from normal imprinting tumors, both in clinical and genetic features.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Ohta
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Motoko
authors.initials: M
authors.lastname: Seto
authors.forename: Dai
authors.initials: D
authors.lastname: Mohri
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Asaoka
authors.forename: Motohisa
authors.initials: M
authors.lastname: Tada
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamaji
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kanai
authors.forename: Takao
authors.initials: T
authors.lastname: Kawabe
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
mesh_terms: D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D018572:Disease-Free Survival; D005260:Female; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051176:beta Catenin / Q000096:biosynthesis; D018631:ras Proteins / Q000235:genetics
chemical_list: C495270:CTNNB1 protein, human; C035170:IGF2 protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins