455 Background: Gastric cancer is the fifth most common malignancy and the fourth leading cause of cancer-related mortality worldwide. Surgical resection with negative margins (R0) remains the cornerstone of curative therapy, yet the prognostic significance of residual disease (R1, R2) may be modified by tumor biology. BRCA2, BRAF, APC, and PTEN are key regulators of DNA repair, cell cycle progression, and tumor suppression, but their interaction with surgical margin outcomes in gastric adenocarcinoma has not been fully defined. Methods: The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) dataset was analyzed for clinical outcomes and RNA-Seq STAR counts for BRCA2, BRAF, APC, and PTEN. Expression was stratified into quartiles, with Q1–2 defined as low expression group (LEG) and Q3–4 as high expression group (HEG). Kaplan–Meier survival analysis was performed across R0, R1, and R2 resections, and survival differences tested by log-rank. Univariate and multivariate Cox proportional hazards models were used to identify predictors, adjusting for race, gender, and AJCC pathologic stage. Results: High expression of all four genes was associated with significantly worse survival in R2 resections. In BRCA2 HEG, R2 predicted poor survival (HR 11.2, 95% CI 5.65–22.1, p <0.001), while R1 was not significant; in the LEG, both R1 (HR 2.47, 95% CI 1.33–4.59, p =0.004) and R2 (HR 3.21, 95% CI 1.84–5.60, p <0.001) were significant. In BRAF HEG, both R1 (HR 2.21, 95% CI 1.32–3.69, p =0.002) and R2 (HR 3.68, 95% CI 2.20–6.13, p <0.001) were significant, while in the LEG only R2 remained highly predictive (HR 49.9, 95% CI 18.2–137, p <0.001). For APC, R2 predicted worse survival in both HEG (HR 3.92, 95% CI 2.41–6.36, p <0.001) and LEG (HR 47.2, 95% CI 16.3–137, p <0.001), while R1 was significant only in LEG (HR 9.90, 95% CI 4.05–24.2, p <0.001). In PTEN HEG, both R1 (HR 3.79, 95% CI 2.33–6.18, p <0.001) and R2 (HR 8.98, 95% CI 5.38–15.0, p <0.001) were significant, whereas in the LEG only R2 retained significance (HR 2.29, 95% CI 1.04–5.06, p =0.040). On multivariate analysis, R2 remained an independent predictor in HEGs for all four genes, while its effect in LEGs was attenuated. Race, sex, and AJCC stage were additional predictors, with White race, male sex, and advanced stages (III–IV) frequently associated with worse survival. Conclusions: High expressions of BRCA2, BRAF, APC, and PTEN amplify the adverse prognostic impact of R2 surgical margins in gastric adenocarcinoma, whereas effects in R0 and R1 resections are gene- and expression-dependent. These findings highlight the interplay between tumor biology and surgical outcomes and suggest that achieving margin-negative resections is especially critical in specific gene expressions.
Ahammed et al. (Sat,) studied this question.