title: The chronological sequence of somatic mutations in early gastric carcinogenesis inferred from multiregion sequencing of gastric adenomas.
abstract: Mutation profiles and intratumoral heterogeneity are not well understood for benign gastric adenomas, some of which progress into malignant gastric adenocarcinomas. In this study, we performed whole-exome sequencing of three microsatellite stable (MSS) and two microsatellite instability-high (MSI-H) gastric adenomas with three regional tumor biopsies per case. We observed that the mutation abundance of benign gastric adenomas was comparable to those of gastric adenocarcinomas, suggesting that the mutational makeup for gastric carcinogenesis may already be achieved in benign adenomas. The extent of intratumoral heterogeneity was more substantial for MSS genomes in that only 1% - 14% of somatic mutations were common across the regional biopsies or 'public', while 50% - 94% of mutations were public in MSI-H gastric adenomas. We observed biallelic, loss-of-functional events of APC with truncating mutations and/or 5q losses for all cases, mostly as public events. All MSS gastric adenomas also harbored ARID2 truncating mutations, often as multiple, region-specific ones indicative of convergent evolution. Hotspot missense mutations on known cancer genes such as ERBB2 and KRAS were largely observed as region-specific aberrations. These findings suggest that biallelic functional APC inactivation initiates the gastric carcinogenesis and is followed by mutations of histone modifiers and then activation of known cancer-related genes. As the first exome-wide multi-region mutational profiling of gastric adenomas, our study provides clues on the chronological sequence of somatic mutations and their clonal architectures in early gastric carcinogenesis.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Chul-Hyun
authors.initials: CH
authors.lastname: Lim
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Yu Kyung
authors.initials: YK
authors.lastname: Cho
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Sang Woo
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Myung-Gyu
authors.initials: MG
authors.lastname: Choi
authors.affiliation: Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Je-Keun
authors.initials: JK
authors.lastname: Rhee
authors.affiliation: Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.|Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.|Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Yeun-Jun
authors.initials: YJ
authors.lastname: Chung
authors.affiliation: Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.|Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Sug-Hyung
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.|Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Tae-Min
authors.initials: TM
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D018256:Adenomatous Polyps; D000368:Aged; D063646:Carcinogenesis / Q000235:genetics; D004252:DNA Mutational Analysis; D059472:Exome; D018628:Gene Dosage; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D006657:Histones; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; C117307:KRAS protein, human; C508053:ERBB2 protein, human
keywords: exome sequencing; gastric adenoma; gastric dysplasia; multiregion sequencing; mutation