Analysis of host pathologic features and genetic factors predisposing to advanced pre-cancerous changes after Helicobacter pylori infection in gastric cancer families

Abstract

Background: To eradicate H pylori before the occurrence of pre-cancerous changes is important to prevent gastric cancer (GCA) GCA exhibits familial clustering and GCA families tend to present with corpus-predominant gastritis and precancerous lesions as spasmolytic polypeptide-expressing metaplasia (SPEM) or intestinal metaplasia (IM) after H pylori infection This study aimed to validate whether corpus-predominant gastritis index (CGI) and host genomic single nucleotide polymorphisms (SNPs) predisposed to gastric carcinogenesis processes in children of GCA patients (GCF) could offer early markers to screen high GCA risk subjects for early H pylori eradication Methods: Totally 389 family relatives of 193 non-cardiac GCA patients and 173 duodenal ulcer (DU) patients as control were included initially Blood samples for DNA extraction were collected to identify SNPs The participants with positive urea breath test (UBT) were invited to receive panendoscope Topographic histology was assessed according to updated Sydney’s system and translated into the operative link on gastritis assessment (OLGA) operative link on gastric intestinal metaplasia assessment (OLGIM) stages and the presence of CGI SPEM identified by immunostaining of trefoil factor 2 (TFF2) and ?5β1 integrin expression were assessed and correlated to the genotype of SNPs within the GCF and verified in GCA patients Results: Both GCA patients and their 1st-degree relatives (1st-degree GCF) had 3-3 4 folds higher prevalence of CGI than the DU controls (p<0 05) Of the 1st-degree GCF the presence of CGI increased 5 5 folds risk of SPEM and 5 7 folds of advanced SPEM (p<0 05) CGI also correlated to corpus shift of bacterial densities and integrin ?5β1 apical distribution The combined genotypes ITGA5-1160T/ITGB1-1949A/ITGB1+31804C and COX-2-1195G/IL-10-592AA was more frequent seen in the GCF than in the DU patients (p<1x10-4) and predisposed to a 5 3-fold risk of SPEM in the H pylori-infected GCF (p= 0 016) Such risk of getting SPEM increased to 112 folds if combined with either or both of RUNX3+492A and TFF2-308CC (p= 1x10-4) The prevalence of CGI tended to decrease in the GCA patients in descending order from no precancerous lesion SPEM only with both IM and SPEM (82%) and IM only (p<0 05) GCA patients without precancerous lesion and with SPEM only had high prevalence of CGI and tended to have younger age female predominant tumor more frequently located at the corpus than the antrum more advanced in stage and poorer differentiation (p<0 05) Within these GCA patients the presence patterns of IM and/or SPEM were closely correlated between the tumor part and non-tumor parts (p<0 001) The GCF with integrin ?5β1 apical distribution at corpus had 8 8 folds-increase risk of advanced SPEM and 29 folds-increase frequency of ITGB1-685-/C/ITGB1-1660AATTT/AATTT/ITGB1+32492G than those without (p= 0 007) This study also found the non-CGI GCA patients with IM only were more frequent to have combinations of SNPs ITGA5-1160GG/TFF2+4649GG and COX-2+8473TT or MMP-9-1562CC than the DU controls (p<0 05) Conclusions: CGI can be early marker to identify H pylori-infected subjects with high GCA risks The combined SNPs of ITGA5-1160T/ITGB1-1949A/ITGB1+31804C and COX-2-1195G/IL-10-592AA predisposed to GCA and may serve as markers to identify high-risk subjects for early H pylori eradication Moreover addition of RUNX3+492A or TFF2-308CC this combined SNPs would greatly facilitate SPEM development In those without CGI combined SNPs ITGA5-1160GG/TFF2+4649GG and COX-2+8473TT or MMP-9-1562CC may offer potential rescue markers worth further investigation

Date of Award	2015 Sept 3
Original language	English
Supervisor	Bor-Shyang Sheu (Supervisor)