Association of human epidermal growth factor receptor 2 (HER2) Ile655Val polymorphism (plrm) and gender-specific time to tumor recurrence (TTR) in patients (pts) with localized gastric adenocarcinoma (GA).

Abstract

Background: Overexpression of members of the HER family (HER1-4) is associated with more aggressive GA. Further evidence is accumulating supporting gender-related differences in the risk, development and outcome of GA. Hormone receptors (ER-(beta)) are expressed in the gastrointestinal tract and interact with HER family. Previous studies found plrms in HER1 and ER-(beta) were associated with gender-specific survival in colorectal cancer pts. HER2 (rs1136201) Ile655Val plrm's functionality was shown in breast cell lines with Val-expressing cells exhibiting increase growth capacity. We tested the hypothesis whether germline plrms in HER family genes, including HER1/EGFR (rs11543848; rs45608036), HER2 (rs1136201), HER3 (rs2271189) and HER4 (rs6735267; rs6735626) plrms, may predict gender-specific clinical outcome in localized GA. Methods: Between 1992 and 2008, normal gastric tissues samples were obtained from 137 pts, 83 males and 54 females, with localized GA treated with surgery alone or surgery and adjuvant (radio)-chemotherapy at USC medical facilities (n = 106) or MSKCC (n = 31). The median follow-up was 3.3 years. 61 out of 137 (41%) pts had tumor recurrence, with a probability of 3-year recurrence of 52%. Genomic DNA was isolated from formalin-fixed paraffin-embedded specimens and 6 HER gene (HER1-4) plrms were analyzed using a PCR-RFLP or a 5'-end 33p (gamma)ATP-labeled PCR technique. Results: HER2 Ile655Val plrm is associated with gender-related TTR (P interaction = 0.02). In multivariate analysis, female pts with the low activity HER2 Ile/Ile (n = 32) genotype have longer TTR when compared to Ile/Val or Val/Val (n = 22) genotypes (median TTR = 7.0 vs. 1.5 years; p = 0.018, log-rank test). In male pts, HER2 Ile655Val plrm is not associated with TTR. No association is observed between other tested HER plrms and TTR. Conclusions: This study shows for the first time the functional HER2 Ile655Val plrm as an independent gender-specific prognostic marker in pts with localized gastric cancer. Prospective biomarker- embedded clinical trials are needed to validate our results.