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Clin Cancer Res. 2018 Oct 1;24(19):4715-4725. doi: 10.1158/1078-0432.CCR-18-0345. Epub 2018 Jun 26.

Clonal Structures of Regionally Synchronous Gastric Adenomas and Carcinomas.

Author information

1
Department of Cancer Evolution Research Center, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.
2
Department of Integrated Research Center for Genome Polymorphism, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.
3
Department of Surgery, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.
4
Department of Hospital Pathology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.
5
Department of Pathology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.
6
Department of Cancer Evolution Research Center, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea. suhulee@catholic.ac.kr yejun@catholic.ac.kr.
7
Department of Microbiology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.

Abstract

Purpose: Gastric adenoma (GA) is a premalignant lesion that precedes intestinal-type gastric carcinoma (GC). However, genetic progression mechanisms from GA to GC have not been clarified.Experimental Design: We performed whole-exome sequencing-based mutational analyses for 15 synchronous pairs of attached GAs and GCs.Results: There was no significant difference in the number of driver mutations or copy-number alterations between GAs and GCs. Well-known mutations of TP53, APC, RNF43, and RPL22 were recurrently detected in synchronous GA/GC pairs. In addition, we discovered novel KDM6A, PREX2, FAT1, KMT2C, GLI3, and RPL22 mutations and hypermutation in GAs, but did not identify recurrent drivers for GA-to-GC progression. Clonal structure analyses revealed that most GA/GC pairs exhibit parallel evolution with early divergence rather than stepwise evolution during GA-to-GC progression. Of note, three cases were identified as clonally nonrelated GA/GC pairs despite the lack of histologic differences. We found differences in dominant mutational signatures 1, 6, 15, and 17 in GA/GC trunks, GA branches, and GC branches. Compared with our previous work on synchronous colon adenoma/carcinoma genome structures, where most drivers were in the trunk with parallel evolution, synchronous GA/GC genomes showed a different model of parallel evolution, with many drivers in the branches.Conclusions: The preferred sequence of mutational events during GA-to-GC progression might be more context-dependent than colon adenoma progression. Our results show that nonclonal synchronous GA/GC is common and that GA genomes have already acquired distinct genomic alterations, suggesting caution in the diagnosis of synchronous GA and GC, especially in residual or recurrent cases. Clin Cancer Res; 24(19); 4715-25. ©2018 AACR.

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