Rokutan Hirofumi, Hosoda Fumie, Hama Natsuko, Nakamura Hiromi, Totoki Yasushi, Furukawa Eisaku, Arakawa Erika, Ohashi Shoko, Urushidate Tomoko, Satoh Hironori, Shimizu Hiroko, Igarashi Keiko, Yachida Shinichi, Katai Hitoshi, Taniguchi Hirokazu, Fukayama Masashi, Shibata Tatsuhiro
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
J Pathol. 2016 Oct;240(2):137-48. doi: 10.1002/path.4761. Epub 2016 Sep 19.
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.
黏液性胃癌（MGC）是一种独特的胃癌亚型，生存预后较差。MGC的综合分子特征和潜在治疗靶点尚未确定。我们对16对肿瘤-正常组织进行了全外显子测序（WES），并对另外52对肿瘤-正常组织进行了后续靶向测序。后者聚焦于WES鉴定出的114个基因。分析了22例组织学分化的MGC（D-MGC）和46例未分化的MGC（U-MGC）。染色质修饰基因，包括ARID1A（21%）、MLL2（19%）、MLL3（15%）和KDM6A（7%），在MGC中频繁发生突变（47%）。我们还在潜在治疗靶点基因中发现了突变，包括MTOR（9%）、BRCA2（9%）、BRCA1（~7%）和ERBB3（6%）。仅在4%的U-MGC中检测到RHOA突变，而D-MGC中未检测到。MYH9在MGC中反复发生突变（13%），所有这些突变均为U-MGC亚型（p = 0.023）。3例U-MGC存在MYH9无义突变。敲低MYH9可增强细胞迁移并诱导胞浆内黏液和细胞伸长。BCOR突变与生存期改善相关。在U-MGC中，MLH1表达状态和联合突变状态（TP53/BCL11B或TP53/MLL2）是预后因素。驱动基因的比较分析显示，D-MGC的突变谱与肠型胃癌相似，而U-MGC是一个独特的实体，其突变谱与肠型和弥漫型胃癌不同。版权所有© 2016英国及爱尔兰病理学会。由John Wiley & Sons, Ltd.出版。
