RAB32 hypermethylation and microsatellite instability in gastric and endometrial adenocarcinomas.
The recently described gene, RAB32, is a ras proto-oncogene family member that encodes an A-kinase-anchoring protein. RAB32 has been found to be frequently hypermethylated in microsatellite instability-high (MSI-H) colon cancers. We sought to determine the prevalence of RAB32 hypermethylation in gastric and endometrial adenocarcinomas, the 2 other major tumor types in which MSI-H is common. Moreover, we delineated the association of RAB32 hypermethylation with microsatellite instability (MSI) and hMLH1 hypermethylation. MSI status and hypermethylation of the RAB32 and hMLH1 genes were studied in paired primary normal and tumor tissues from 48 patients with gastric cancer. An additional 80 endometrial cancer patients were studied for RAB32 methylation and MSI status. Thirteen (27%) of 48 gastric cancers demonstrated evidence of RAB32 hypermethylation. MSI status was determined in 46 of the tumors, with 7 (100%) of 7 MSI-H tumors, 1 (33%) of 3 MSI-low (MSI-L) tumors and 4 (11%) of 36 microsatellite-stable (MSS) tumors found to harbor RAB32 hypermethylation. RAB32 methylation was significantly associated with intestinal type histology and concomitant hMLH1 hypermethylation in gastric cancer. In contrast, RAB32 methylation occurred in only 1 of 80 endometrial cancers, including 20 MSI-H, 8 MSI-L and 52 MSS tumors. Hypermethylation of hMLH1 was noted in 16 (20%) of 80 endometrial tumors. We conclude that although RAB32 methylation is rare in endometrial cancers, it is strongly associated with hMLH1 hypermethylation and MSI in gastric adenocarcinomas. Given its similar involvement in colon cancer, RAB32 inactivation may represent a component of the oncogenic pathway of microsatellite-unstable gastrointestinal adenocarcinomas.
Division of Gastrointestinal Oncology, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, FL 33612, USA. shibatd@moffitt.usf.edu
David
D
Shibata
Yuriko
Y
Mori
Kun
K
Cai
Li
L
Zhang
Jing
J
Yin
Abul
A
Elahi
Richard
R
Hamelin
Yick F
YF
Wong
Wing K
WK
Lo
Tony K H
TK
Chung
Fumiaki
F
Sato
Martin S
MS
Karpeh
Stephen J
SJ
Meltzer
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000378:metabolism; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D013274:Stomach Neoplasms / Q000235:genetics*; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C000715470:MAS1 protein, human; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; C466094:Rab32 protein, human; D000070957:MutL Protein Homolog 1; D020691:rab GTP-Binding Proteins