RAB32 hypermethylation and microsatellite instability in gastric and endometrial adenocarcinomas

Abstract

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. ' 2006 Wiley-Liss, Inc.Key words: RAB32; methylation; microsatellite instability; gastric cancer; endometrial cancer Hypermethylation of promoter region CpG islands is well recognized as an important mechanism of transcriptional repression and loss of gene function. 1 As a key example, hypermethylation of hMLH1 is strongly associated with sporadic cases of microsatellite instability-high (MSI-H) cancers. There is growing evidence to suggest that concurrent hypermethylation of multiple additional genes may represent an important component in the development and progression of colorectal cancers. [2][3][4][5][6][7][8] This propensity for methylation in such tumors has served as an interesting feature to exploit in the search for novel methylation targets.We have recently applied a global expression profiling-based technique to identify potential novel methylation targets in MSI-H colorectal cancers. One of the genes discovered to have significant differential methylation in microsatellite-unstable cancers was RAB32, a mitochondrial ras family member that encodes an A-kinase anchoring protein. RAB32 was found to be methylated exclusively in MSI-H colon cancers, with no evidence of methylation in either non-MSI-H tumors or normal adjacent mucosal tissue. 9 RAB32 has the ability to anchor the cyclic ...

Identification of novel neuroendocrine-specific tumour genes

“…FOSL1 is upregulated in several solid cancers, and is becoming a new target for cancer intervention (Young and Colburn 2006). The ras family member RAB32, has been proposed to represent a component of the oncogenic pathway of microsatellite instabilityhigh gastrointestinal adenocarcinomas (Shibata et al, 2006). In our study, RAB32 was highly downregulated in the NE vs the non-NE group.…”

NORE1A Tumor Suppressor Candidate Modulates p21CIP1 via p53

“…Among them, BTG3 is a putative tumor suppressor and target of p53 itself (28), and PDCD2 has been implicated in apoptosis (29) and proliferation control (30). Moreover, RAB32 down-regulation has been associated with colon cancer (31). Thus, NORE1A promotes a number of alterations in transcription that might be expected to repress transformation.…”

Disrupted RabGAP Function of the p85 Subunit of Phosphatidylinositol 3-Kinase Results in Cell Transformation

“…Rab20 is expressed in pancreatic cancer (39), and although the function of Rab20 is not well characterized, it is known to localize near the Golgi body and apical plasma membranes, suggesting that it may regulate trafficking between these two membranes (39,40). The rab32 gene is hypermethylated in gastric and endometrial adenocarcinomas (41). The Rab32 protein is involved in mitochondrial fission and anchoring protein kinase A to membranes (42).…”