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. 2009 Feb;136(2):640-51.e1.
doi: 10.1053/j.gastro.2008.10.050. Epub 2008 Oct 29.

Methylation of protocadherin 10, a novel tumor suppressor, is associated with poor prognosis in patients with gastric cancer

Jun Yu  1 , Yuen Y Cheng, Qian Tao, Kin F Cheung, Cleo N Y Lam, Hua Geng, Lin-Wei Tian, Ying P Wong, Joanna H M Tong, Jian-Ming Ying, Hongchuan Jin, Ka F To, Francis K L Chan, Joseph J Y Sung
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Methylation of protocadherin 10, a novel tumor suppressor, is associated with poor prognosis in patients with gastric cancer

Jun Yu et al. Gastroenterology. 2009 Feb.

Abstract

Background & aims: By using methylation-sensitive representational difference analysis, we identified protocadherin 10 (PCDH10), a gene that encodes a protocadherin and is silenced in a tumor-specific manner. We analyzed its epigenetic inactivation, biological effects, and prognostic significance in gastric cancer.

Methods: Methylation status was evaluated by combined bisulfite restriction analysis and bisulfite sequencing. The effects of PCDH10 re-expression were determined in growth, apoptosis, proliferation, and invasion assays. PCDH10 target genes were identified by complementary DNA microarray analysis.

Results: PCDH10 was silenced or down-regulated in 94% (16 of 17) of gastric cancer cell lines; expression levels were restored by exposure to demethylating agents. Re-expression of PCDH10 in MKN45 gastric cancer cells reduced colony formation in vitro and tumor growth in mice; it also inhibited cell proliferation (P < .01), induced cell apoptosis (P < .001), and repressed cell invasion (P < .05), up-regulating the pro-apoptosis genes Fas, Caspase 8, Jun, and CDKN1A; the antiproliferation gene FGFR; and the anti-invasion gene HTATIP2. PCDH10 methylation was detected in 82% (85 of 104) of gastric tumors compared with 37% (38 of 104) of paired nontumor tissues (P < .0001). In the latter, PCDH10 methylation was higher in precancerous lesions (27 of 45; 60%) than in chronic gastritis samples (11 of 59; 19%) (P < .0001). After a median follow-up period of 16.8 months, multivariate analysis revealed that patients with PCDH10 methylation in adjacent nontumor areas had a significant decrease in overall survival. Kaplan-Meier survival curves showed that PCDH10 methylation was associated significantly with shortened survival in stage I-III gastric cancer patients.

Conclusions: PCDH10 is a gastric tumor suppressor; its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.

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