Comprehensive mutation profiling of mucinous gastric carcinoma.
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.
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.|Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hirofumi
H
Rokutan
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Fumie
F
Hosoda
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Natsuko
N
Hama
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Hiromi
H
Nakamura
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Yasushi
Y
Totoki
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Eisaku
E
Furukawa
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Erika
E
Arakawa
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Shoko
S
Ohashi
Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Tomoko
T
Urushidate
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Hironori
H
Satoh
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Hiroko
H
Shimizu
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Keiko
K
Igarashi
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Shinichi
S
Yachida
Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
Hitoshi
H
Katai
Pathology Division, National Cancer Center Hospital, Tokyo, Japan.
Hirokazu
H
Taniguchi
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Masashi
M
Fukayama
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. tshibata@ims.u-tokyo.ac.jp, tashibat@ncc.go.jp.|Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. tshibata@ims.u-tokyo.ac.jp, tashibat@ncc.go.jp.
Tatsuhiro
T
Shibata
D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
MYH9; chromatin modifiers; exome sequencing; mucinous gastric carcinoma; stomach