Genomic and Epigenomic Profiling of High-Risk Intestinal Metaplasia Reveals Molecular Determinants of Progression to Gastric Cancer
Genomic and Epigenomic Profiling of High-Risk Intestinal Metaplasia Reveals Molecular Determinants of Progression to Gastric Cancer
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DOI：
10.1016/j.ccell.2017.11.018
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发表时间：
2018-01-01
期刊：
影响因子：
50.3
通讯作者：
Tan, Patrick
中科院分区：
文献类型：
--
作者：
Huang, Kie Kyon;Ramnarayanan, Kalpana;Tan, Patrick
肠上皮化生（IM）是一种与胃癌（GC）风险增加相关的胃粘膜癌前病变。我们对来自148名无癌症患者的138个IM进行了（epi）基因组分析，这些患者是通过一项为期10年的前瞻性研究招募的。与GC相比，IM表现出较低的突变负荷，某些肿瘤抑制因子（FBXW 7）而不是其他肿瘤抑制因子（TP 53，ARID 1A）的复发突变，染色体8 q扩增和缩短的端粒。与组织病理学相比，测序鉴定出更多的活动性幽门螺杆菌感染的IM患者（11%-27%）。一些IM在DNA甲基化谷表现出高甲基化;然而，IM通常缺乏晚期恶性肿瘤的基因内低甲基化特征。端粒缩短和染色体改变的IM患者与随后的异型增生或GC相关;相反，表现出正常样表观基因组模式的患者与消退相关。
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.