Comprehensive mutation profiling of mucinous gastric carcinoma. Issue 2 (19th September 2016) - Rokutan, Hirofumi
Abstract: Mucinous gastric carcinoma (MGC) is a unique subtype of gastric cancer with a poor survival outcome. Comprehensive molecular profiles and putative therapeutic targets of MGC remain undetermined. We subjected 16 tumour‐normal tissue pairs to whole‐exome sequencing (WES) and an expanded set of 52 tumour‐normal tissue pairs to subsequent targeted sequencing. The latter focused on 114 genes identified by WES. Twenty‐two histologically differentiated MGCs (D‐MGCs) and 46 undifferentiated MGCs (U‐MGCs) were analysed. Chromatin modifier genes, including ARID1A (21%), MLL2 (19%), MLL3 (15%), and KDM6A (7%), were frequently mutated (47%) in MGC. We also identified mutations in potential therapeutic target genes, including MTOR (9%), BRCA2 (9%), BRCA1 (7%), and ERBB3 (6%). RHOA mutation was detected only in 4% of U‐MGCs and in no D‐MGCs. MYH9 was recurrently (13%) mutated in MGC, with all these being of the U‐MGC subtype ( p = 0.023). Three U‐MGCs harboured MYH9 nonsense mutations. MYH9 knockdown enhanced cell migration and induced intracytoplasmic mucin and cellular elongation. BCOR mutation was associated with improved survival. In U‐MGCs, the MLH1 expression status and combined mutation status ( TP53/BCL11B or TP53/MLL2 ) were prognostic factors. A comparative analysis of driver genes revealed that the mutation profile of D‐MGC was similar to that of intestinal‐type gastric cancer, whereas U‐MGC was a distinct entity, harbouring a different mutational profile to intestinal‐ and diffuse‐type gastric cancers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.