Tamotsu Sugai1, Wataru Habano2, Ryo Takagi3, Hiroo Yamano3, Makoto Eizuka4, Noriyuki Arakawa4, Yayoi Takahashi4, Eiichiro Yamamoto5,6, Keisuke Kawasaki7, Syunichi Yanai7, Kazuyuki Ishida4, Hiromu Suzuki5, Takayuki Matsumoto7. 1. Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Morioka, 020-8505, Japan. tsugai@iwate-med.ac.jp. 2. Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 19-1, Morioka, 020-8505, Japan. 3. Division of Gastroenterology, Akita Red Cross Hospital, Kamikitatesaruta, Akita, 010-1406, Japan. 4. Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Morioka, 020-8505, Japan. 5. Department of Molecular Biology, Sapporo Medical University, Minami1jonishi 1-19, Chuo-ku, Sapporo, Hokkaido, 060-0061, Japan. 6. Department of First Internal Medicine, Sapporo Medical University, Minami1jonishi 1-19, Chuo-ku, Sapporo, Hokkaido, 060-0061, Japan. 7. Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, 19-1, Morioka, 020-8505, Japan.
Abstract
BACKGROUND: Colorectal laterally spreading tumors (LSTs) are classified into LST-Gs and LST-NGs, according to macroscopic findings. In the present study, we determined the genetic and epigenetic alterations within colorectal LSTs and protruding adenomas. METHODS: A crypt isolation method was used to isolate DNA from tumors and normal glands of 73 macroscopically verified colorectal LSTs (histologically defined adenomas; 38 LST-Gs and 35 LST-NGs) and 36 protruding adenomas. The DNA was processed using polymerase chain reaction (PCR) microsatellite assays, single-strand conformation polymorphism (SSCP) assays, and pyrosequencing to detect chromosomal allelic imbalance (AI), mutations in APC, KRAS, and TP53, and the methylation of MLH1, MGMT, CDKN2A, HPP1, RASSF2A, SFRP1, DKK1, ZFP64, and SALL4 genes. In addition, methylation status was examined using the following set of markers: MIN1, MINT2, MINT31, MLH1, and CDKN2A (with classification of negative/low and high). Microsatellite instability (MSI) was also examined. RESULTS: 5q AI and methylation of the SFRP1 and SALL4 genes were common molecular events in both LST-Gs and LST-NGs. Neither MSI nor mutations in BRAF ware observed in the LSTs. TP53 mutations were rarely found in LSTs. The frequencies of KRAS and APC mutations and the methylation levels of ZFP64, RASSF2A, and HPP1 genes were significantly higher in LST-Gs than in LST-NGs. Protruding adenomas showed alterations common to LST-Gs. Negative/low methylation status was common among the three types of tumors. CONCLUSION: Combined genetic and epigenetic data suggested that the molecular mechanisms of tumorigenesis were different between LST-Gs and LST-NGs.
BACKGROUND: Colorectal laterally spreading tumors (LSTs) are classified into LST-Gs and LST-NGs, according to macroscopic findings. In the present study, we determined the genetic and epigenetic alterations within colorectal LSTs and protruding adenomas. METHODS: A crypt isolation method was used to isolate DNA from tumors and normal glands of 73 macroscopically verified colorectal LSTs (histologically defined adenomas; 38 LST-Gs and 35 LST-NGs) and 36 protruding adenomas. The DNA was processed using polymerase chain reaction (PCR) microsatellite assays, single-strand conformation polymorphism (SSCP) assays, and pyrosequencing to detect chromosomal allelic imbalance (AI), mutations in APC, KRAS, and TP53, and the methylation of MLH1, MGMT, CDKN2A, HPP1, RASSF2A, SFRP1, DKK1, ZFP64, and SALL4 genes. In addition, methylation status was examined using the following set of markers: MIN1, MINT2, MINT31, MLH1, and CDKN2A (with classification of negative/low and high). Microsatellite instability (MSI) was also examined. RESULTS: 5q AI and methylation of the SFRP1 and SALL4 genes were common molecular events in both LST-Gs and LST-NGs. Neither MSI nor mutations in BRAF ware observed in the LSTs. TP53 mutations were rarely found in LSTs. The frequencies of KRAS and APC mutations and the methylation levels of ZFP64, RASSF2A, and HPP1 genes were significantly higher in LST-Gs than in LST-NGs. Protruding adenomas showed alterations common to LST-Gs. Negative/low methylation status was common among the three types of tumors. CONCLUSION: Combined genetic and epigenetic data suggested that the molecular mechanisms of tumorigenesis were different between LST-Gs and LST-NGs.
Entities:
Keywords:
APC; Colon; KRAS; Laterally spreading tumor; Loss of heterozygosity; Methylation
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