Analysis of molecular alterations in laterally spreading tumors of the colorectum

• Published in: Journal of gastroenterology 2017-06, Vol.52 (6), p.715-723
• Main Authors: Sugai, Tamotsu, Habano, Wataru, Takagi, Ryo, Yamano, Hiroo, Eizuka, Makoto, Arakawa, Noriyuki, Takahashi, Yayoi, Yamamoto, Eiichiro, Kawasaki, Keisuke, Yanai, Syunichi, Ishida, Kazuyuki, Suzuki, Hiromu, Matsumoto, Takayuki
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Adenoma - genetics; Adenoma - pathology; Adenomatous polyposis coli; Adult; Aged; Aged, 80 and over; Analysis; Classification; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Colorectal Surgery; Conformation; Dkk1 protein; DNA Methylation; DNA, Neoplasm - genetics; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Female; Frizzled-related protein 1; Gastroenterology; Genes; Genetic aspects; Genetic polymorphisms; Glands; Hepatology; Humans; K-Ras protein; Male; Medicine; Medicine & Public Health; Methylation; Microsatellite Instability; Middle Aged; MLH1 protein; Molecular modelling; Mutation; Original Article—Alimentary Tract; p53 Protein; Polymerase Chain Reaction; Spreading; Surgical Oncology; Tumor proteins; Tumorigenesis; Tumors
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-016-1269-y

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.