Genomic and Epigenomic Profiling of High-Risk Intestinal Metaplasia Reveals Molecular Determinants of Progression to Gastric Cancer
Kie Kyon Huang, Kalpana Ramnarayanan, Feng Zhu, Supriya Srivastava, Chang Xu, Angie Lay Keng Tan, Minghui Lee, Suting Tay, Kakoli Das, Manjie Xing, Aliya Fatehullah, Syed Muhammad Fahmy Alkaff, Tony Kiat Hon Lim, Jonathan Lee, Khek Yu Ho, Steven George Rozen, Bin Tean Teh, Nick Barker, Chung King Chia, Christopher Khor, Choon Jin Ooi, Kwong Ming Fock, Jimmy So, Wee Chian Lim, Khoon Lin Ling, Tiing Leong Ang, Andrew Wong, Jaideepraj Rao, Andrea Rajnakova, Lee Guan Lim, Wai Ming Yap, Ming Teh, Khay Guan Yeoh, Patrick Tan, Kie Kyon Huang, Kalpana Ramnarayanan, Feng Zhu, Supriya Srivastava, Chang Xu, Angie Lay Keng Tan, Minghui Lee, Suting Tay, Kakoli Das, Manjie Xing, Aliya Fatehullah, Syed Muhammad Fahmy Alkaff, Tony Kiat Hon Lim, Jonathan Lee, Khek Yu Ho, Steven George Rozen, Bin Tean Teh, Nick Barker, Chung King Chia, Christopher Khor, Choon Jin Ooi, Kwong Ming Fock, Jimmy So, Wee Chian Lim, Khoon Lin Ling, Tiing Leong Ang, Andrew Wong, Jaideepraj Rao, Andrea Rajnakova, Lee Guan Lim, Wai Ming Yap, Ming Teh, Khay Guan Yeoh, Patrick Tan
Abstract
Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We performed (epi)genomic profiling of 138 IMs from 148 cancer-free patients, recruited through a 10-year prospective study. Compared with GCs, IMs exhibit low mutational burdens, recurrent mutations in certain tumor suppressors (FBXW7) but not others (TP53, ARID1A), chromosome 8q amplification, and shortened telomeres. Sequencing identified more IM patients with active Helicobacter pylori infection compared with histopathology (11%-27%). Several IMs exhibited hypermethylation at DNA methylation valleys; however, IMs generally lack intragenic hypomethylation signatures of advanced malignancy. IM patients with shortened telomeres and chromosomal alterations were associated with subsequent dysplasia or GC; conversely patients exhibiting normal-like epigenomic patterns were associated with regression.
Keywords: Helicobacter pylori; cancer genomics; gastric cancer; intestinal metaplasia; risk stratification.
Copyright © 2017 Elsevier Inc. All rights reserved.
Source: PubMed