DNA Methylation Predicts Progression of Human Gastric Lesions

Abstract

Background Development of the intestinal subtype of gastric adenocarcinoma is marked by a progression of histopathological lesions. Residents of the Andean regions of Colombia are at high risk for gastric cancer. Methods A cohort of 976 Colombian subjects was followed over 16 years examining effects of Helicobacter pylori eradication and treatment with anti-oxidants on progression of lesions. We performed methylation analysis of DNA from baseline antral biopsies from 104 subjects for whom follow-up data were available for at least 12 years. Methylation was quantitated for AMPH, CDKN2A, CDH1, EN1, EMX1, NKX6-1, PCDH10, RPRM, RSPO2, SORCS3, ZIC1, and ZNF610 genes, using Pyrosequencing. Results Levels of DNA methylation were associated with baseline diagnosis for AMPH, EMX1, RPRM, RSPO2, SORCS3 and ZNF610. After adjusting for baseline diagnosis and H. pylori infection, methylation levels of AMPH, PCDH10, RSPO2 and ZNF610 had progression coefficients that increased and p values that decreased over 6, 12 and 16 years. Methylation for SORCS3 was associated with progression at all 3 time points, but without the continual strengthening of the effect. Scores for mononuclear leukocytes, polymorphonuclear leukocytes or intraepithelial lymphocytes were unrelated to progression. Conclusions Methylation levels of AMPH, PCDH10, RSPO2, SORCS3 and ZNF610 predict progression of gastric lesions independent of the effect of duration of H. pylori infection, baseline diagnosis, gender of the patient, or scores for mononuclear leukocytes, polymorphonuclear leukocytes or intraepithelial lymphocytes. Impact DNA methylation levels in AMPH, PCDH10, RSPO2, SORCS3 and ZNF610 may contribute to identification of persons with gastric lesions likely to progress.

The Immune Battle against Helicobacter pylori Infection: NO Offense

“…Moreover, the common trait of H. pylori strains that have increased risk of inducing gastric adenocarcinoma is the expression of specific virulence genes including the protein cytotoxin-associated gene A (CagA) [2] and the vacuolating cytotoxin A (VacA) [3] (Box1). Environmental components [4] and host factors [5] have been also shown to be involved in the outcome of H. pylori infection. But, whether host and pathogen genomic variations in a spatio-temporal axis are associated with the development of gastric diseases, overall the clinical outcome of H. pylori infection-induced gastric carcinogenesis is determined by the progression along the histologic cascade from non-atrophic gastritis to adenocarcinoma [6].…”

Epigenetic and genetic variation in GATA5 is associated with gastric disease risk

“…In the replication cohort and methylation group, for 104 subjects for whom single colony cultures were not available, the vacA s region was characterized from biopsy DNA as previously described (Schneider et al 2015). …”

“…Many changes in DNA methylation occur non-specifically, as a function of aging or environmental factors (Teschendorff et al 2010). Some changes may occur in premalignant lesions, making methylation changes potentially useful as biomarkers of gastric cancer risk (Schneider et al 2015; Watanabe et al 2009). …”

The homeobox NKX and Neoplasms in Digestive system: a systematic review.

“…At same period, a cross-sectional study that also conducted by Asada and Shimazu suggested that NKX6.1 methylation level is closely associated with the risk of gastric cancer incidence [82] . At almost same period, Schneider held a cohort for over 16 years in Colombia, claimed that the level of NKX6.1 DNA methylation was associated with gastric cancer progression, further illustrates that epigenetic modification may affect NKX6.1 expression level in tumor [83] . From the studies we mentioned before, NKX6.1 may be involved in the development of WDNETs, HCC, or gastric cancer, whereas more functional experiments in vivo and vitro are required to confirm the theoretical hypothesis.…”