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Reprimo as a Potential Biomarker for Early Detection in Gastric Cancer

Authors' Affiliations: ¹ Department of Anatomic Pathology and ² Laboratory of Molecular Pathology and Epidemiology, Centro Investigaciones Medicas, Pontificia Universidad Católica de Chile, ³ Instituto Chileno Japonés de Enfermedades Digestivas Hospital Clínico San Borja Arriaran, and ⁴ Department of Internal Medicine, Campus Centro, Universidad de Chile, Santiago, Chile

Requests for reprints: Alejandro H. Corvalan, Department of Pathology, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030. Phone: 713-563-9202; Fax: 713-792-0309; E-mail: acorvala{at}mdanderson.org.

Purpose: Gastric cancer is a curable disease if diagnosed at early stage. However, most cases are diagnosed at advanced stage because of the lack of screening programs. Therefore, the identification of plasma biomarkers for early detection is necessary.

Experimental Design: To search for these biomarkers, we evaluated the DNA methylation patterns of 24 genes by Methylation-specific PCR in primary tissues from 32 retrospectively collected gastric cancer cases (testing group). Correlation between methylation and gene expression was evaluated in the MKN-45 cell line after treatment with 5-aza-2'-deoxycytidine. The most frequently hypermethylated genes were next evaluated in primary tissues and plasma samples from 43 prospectively collected gastric cancer cases as well as plasma samples from 31 asymptomatic age- and gender-matched controls (validation group).

Results: In the testing group, 11 genes were hypermethylated in at least 50% of cases (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, 3OST2, p14, p15, DAPK, and p16). Eight genes (BRCA1, p73, RARβ, hMLH1, RIZI, RUNX3, MGMT, and TIMP3) were statistically associated with a particular variant of gastric cancer, the signet-ring cell type (P = 0.03). Seven genes (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, and 3OST2) were next evaluated in the validation group. We confirm the high frequency of methylation in primary tumors for all seven genes. However, only APC and Reprimo were frequently methylated in pair plasma samples. In asymptomatic controls, only Reprimo was infrequently methylated in comparison with plasma from gastric cancer cases (P < 0.001).

Conclusion: Our results identified specific methylation profile associated to signet-ring cell-type histology and aberrant hypermethylation of Reprimo as a potential biomarker for early detection of gastric cancer.