DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: a comprehensive profiling approach

BMC Gastroenterology

Research Article

Aparna Vaithilingam¹  Nur Sabrina Sapari¹  Eiram Elahi¹  Zuan Yu Mok¹  Richie Soong²  Manuel Salto-Tellez³  Natalia Liem⁴  Pei Li Lim⁴  Marie Loh⁵  Brendan Pang⁶  Chee Leong Cheng⁶  Benedict Yan⁶  Wei Peng Yong⁷  Barry Iacopetta⁸ 

[1] Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore;Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore;Department of Pathology, National University Health System, Singapore, Singapore;Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore;Department of Pathology, National University Health System, Singapore, Singapore;Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK;Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore;National University Cancer Institute of Singapore, National University Health System, Singapore, Singapore;Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore;School of Surgery, The University of Western Australia, Perth, Australia;Department of Epidemiology and Biostatistics, Imperial College London, London, UK;Institute of Health Sciences, University of Oulu, Oulu, Finland;Department of Pathology, National University Health System, Singapore, Singapore;National University Cancer Institute of Singapore, National University Health System, Singapore, Singapore;School of Surgery, The University of Western Australia, Perth, Australia;

关键词: Methylation;    Gastric cancer;    Microarray;    CIMP;    GoldenGate;   

DOI  :  10.1186/1471-230X-14-55

 received in 2013-08-02, accepted in 2014-03-25,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundMethylation-induced silencing of promoter CpG islands in tumor suppressor genes plays an important role in human carcinogenesis. In colorectal cancer, the CpG island methylator phenotype (CIMP) is defined as widespread and elevated levels of DNA methylation and CIMP+ tumors have distinctive clinicopathological and molecular features. In contrast, the existence of a comparable CIMP subtype in gastric cancer (GC) has not been clearly established. To further investigate this issue, in the present study we performed comprehensive DNA methylation profiling of a well-characterised series of primary GC.MethodsThe methylation status of 1,421 autosomal CpG sites located within 768 cancer-related genes was investigated using the Illumina GoldenGate Methylation Panel I assay on DNA extracted from 60 gastric tumors and matched tumor-adjacent gastric tissue pairs. Methylation data was analysed using a recursively partitioned mixture model and investigated for associations with clinicopathological and molecular features including age, Helicobacter pylori status, tumor site, patient survival, microsatellite instability and BRAF and KRAS mutations.ResultsA total of 147 genes were differentially methylated between tumor and matched tumor-adjacent gastric tissue, with HOXA5 and hedgehog signalling being the top-ranked gene and signalling pathway, respectively. Unsupervised clustering of methylation data revealed the existence of 6 subgroups under two main clusters, referred to as L (low methylation; 28% of cases) and H (high methylation; 72%). Female patients were over-represented in the H tumor group compared to L group (36% vs 6%; P = 0.024), however no other significant differences in clinicopathological or molecular features were apparent. CpG sites that were hypermethylated in group H were more frequently located in CpG islands and marked for polycomb occupancy.ConclusionsHigh-throughput methylation analysis implicates genes involved in embryonic development and hedgehog signaling in gastric tumorigenesis. GC is comprised of two major methylation subtypes, with the highly methylated group showing some features consistent with a CpG island methylator phenotype.

【 授权许可】

Unknown   
© Loh et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.