Clonal Structures of Regionally Synchronous Gastric Adenomas and Carcinomas.

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> We performed whole-exome sequencing-based mutational analyses for 15 synchronous pairs of attached GAs and GCs.<b>Results:</b> There was no significant difference in the number of driver mutations or copy-number alterations between GAs and GCs. Well-known mutations of <i>TP53, APC, RNF43,</i> and <i>RPL22</i> were recurrently detected in synchronous GA/GC pairs. In addition, we discovered novel <i>KDM6A, PREX2, FAT1, KMT2C, GLI3,</i> and <i>RPL22</i> 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.<b>Conclusions:</b> 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. <i>Clin Cancer Res; 24(19); 4715-25. ©2018 AACR</i>.