Oncotarget

Research Papers:

The chronological sequence of somatic mutations in early gastric carcinogenesis inferred from multiregion sequencing of gastric adenomas

Chul-Hyun Lim _, Yu Kyung Cho, Sang Woo Kim, Myung-Gyu Choi, Je-Keun Rhee, Yeun-Jun Chung, Sug-Hyung Lee and Tae-Min Kim

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Oncotarget. 2016; 7:39758-39767. https://doi.org/10.18632/oncotarget.9250

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Abstract

Chul-Hyun Lim1, Yu Kyung Cho1, Sang Woo Kim1, Myung-Gyu Choi1, Je-Keun Rhee2, Yeun-Jun Chung3,4,5, Sug-Hyung Lee3,6, Tae-Min Kim2,7

1Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

2Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

3Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

4Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

5Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

6Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

7Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

Correspondence to:

Tae-Min Kim, e-mail: tmkim@catholic.ac.kr

Keywords: gastric adenoma, gastric dysplasia, exome sequencing, mutation, multiregion sequencing

Received: March 01, 2016    Accepted: April 26, 2016    Published: May 09, 2016

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.


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