Clonal Structures of Regionally Synchronous Gastric Adenomas and Carcinomas
| Autor: | Seung-Hyun Jung, Eun Sun Jung, Sug Hyung Lee, Chang Hyeok An, Hyeon-Chun Park, Sung Hak Lee, Min Sung Kim, Yeun-Jun Chung, Shin Young Kim |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adenoma
Male 0301 basic medicine Cancer Research DNA Copy Number Variations Carcinogenesis Colon Adenoma Somatic hypermutation Genomics Biology medicine.disease_cause Genome Clonal Evolution 03 medical and health sciences 0302 clinical medicine Stomach Neoplasms Exome Sequencing medicine Carcinoma Humans Exome Exome sequencing Aged Aged 80 and over Genetics Mutation Cancer Middle Aged medicine.disease Neoplasm Proteins Gene Expression Regulation Neoplastic 030104 developmental biology Oncology 030220 oncology & carcinogenesis Disease Progression Female |
| Zdroj: | Clinical Cancer Research. 24:4715-4725 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-18-0345 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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