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Τρίτη 26 Ιουνίου 2018

Clonal structures of regionally synchronous gastric adenomas and carcinomas

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 non-related 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 to 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 non-clonal 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.



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