Somatic DNA Hypomethylation in H. pylori-Associated High-Risk Gastritis and Gastric Cancer: Enhanced Somatic Hypomethylation Associates with Advanced Stage Cancer.
OBJECTIVE
Helicobacter pylori-related high-risk gastritis (HRG) is a severe risk factor for gastric cancer (GC). The link between HRG and long-term risk for GC may involve genetic and epigenetic alterations underlying a field defect, i.e. a region of the mucosa prone to cancer development. Global DNA hypomethylation is a pervasive alteration in GC that associates with chromosomal instability and poor prognosis. The aim of this study was to determine the chronology of this alteration along the progression of HRG to GC, to test the hypothesis that it occurs early in the chronology of this pathway and plays a mechanistic role in the long-term cancer risk.


METHODS
We comparatively measured the genomic methylation level in gastric biopsies from 94 GC patients and 16 of their cancer-free relatives, 38 HRG patients, and 17 GERD patients, using a quantitative enzymatic method.


RESULTS
GC biopsies were hypomethylated compared to their matching non-tumor mucosa (P=9.4 × 10(-12)), irrespective of the tumor location or patients' country of origin. Genome-wide hypomethylation was also found in gastric mucosa of GC (P=1.5 × 10(-5)) and HRG (P=0.004) patients compared with healthy donors and GC relatives, regardless of the biopsy location within the stomach or previous H. pylori eradication therapy. An enhanced hypomethylation, distinguished by a bi-slope distribution of the differences in methylation between tumor and normal tissues, associated with a more invasive (P=0.005) and advanced stage (P=0.017) type of GC.


CONCLUSIONS
Universal DNA demethylation in normal gastric mucosa in GC patients appears sporadic rather than familial. Genomic hypomethylation in HRG possibly contributes to a field defect for cancerization that is not reversed by bacterial eradication. Enhanced somatic hypomethylation may stratify GC for prognostic purposes.
1] Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA [2] Department of Internal Medicine, Ev. Hospital, Herne, Germany.
Andreas
A
Leodolter
1] Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA [2] Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain.
Sergio
S
Alonso
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain.
Beatriz
B
González
Department of Internal Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
Matthias P
MP
Ebert
Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany.
Michael
M
Vieth
Department of Pathology, Christian-Albrechts University, Kiel, Germany.
Christoph
C
Röcken
Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.
Thomas
T
Wex
Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.
Ullrich
U
Peitz
Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.
Peter
P
Malfertheiner
1] Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA [2] Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain [3] Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Manuel
M
Perucho