Low BUB1 expression is an adverse prognostic marker in gastric adenocarcinoma

Abstract

Gastric adenocarcinomas are associated with a poor prognosis due to the fact that the tumor has often metastasized by the time of diagnosis and prognostic markers are urgently needed to tailor treatment. We examined the expression of the mitotic spindle checkpoint protein BUB1 (budding uninhibited by benzimidazoles 1) and Ki-67 protein expression by immunohistochemistry in 218 patients with primary gastric adenocarcinomas. Tumors with low frequency of BUB1 expression were associated with larger tumor size (pT) (p < 0.001), higher incidence of lymph node metastases (pN) (p = 0.027), distant metastases (pM) (p = 0.006) and higher UICC stage (p < 0.001). Furthermore, BUB1 expression was inversely correlated with residual tumor stage (p = 0.038). Abundant BUB1 protein expression correlated with frequent Ki-67 protein expression (p < 0.001) and low BUB1 expression was associated with shorter survival (p < 0.001). Univariate and multivariate analyses confirmed BUB1 to be an independent prognostic marker in gastric cancer (p = 0.021).

Keywords: BUB1; biomarker; gastric adenocarcinoma; gastric cancer; immunohistochemistry.

Figure 1. BUB1 and Ki-67 expression in gastric adenocarcinoma

Low (B), medium (E) and high (H) BUB1 staining with corresponding H&E (A, D, G) and Ki-67 (C, F, I) IHC staining (original magnification x400) in gastric cancer. Scale bar representing 100 μm.

Figure 2. Correlation of BUB1 and Ki-67 expression

(r = 0.580, p < 0.001, Spearman rank test).

Figure 3. Overall survival in patients with gastric adenocarcinoma is dependent on BUB1 expression

Kaplan-Meier analysis with follow-up data available for 148 out of 218 cases. (A) Two-tier BUB1 analysis. Low BUB1 expression (<16% of tumor nuclei) (blue curve) with a median OS of 17 months (95% CI, 10.747-23.254 months), high BUB1 expression (>16% of tumor nuclei) (green curve) with an estimated median survival of 48 months (95% CI, 23.445-72.555 months) (p < 0.001, log-rank test). (B) Four-tier BUB1 analysis. Low BUB1 expression (<8%) (blue curve) with a median OS of 8 months (95% CI, 3.238-12.762 months), medium-low BUB1 expression (8%-16%) (green curve) with a median OS of 26 months (95% CI, 13.151-38.849 months), medium-high expression (16%-28%) (purple curve) with a median OS of 25 months (95% CI, 9.577-40.423 months), high BUB1 expression (>28%) (red curve) with an estimated median survival of 65 months (95% CI, 49.375-80.625 months) (p < 0.001, log-rank test). (C) Three-tier BUB1 analysis. Low BUB1 expression (<8%) (blue curve) with a median OS of 8 months (95% CI, 3.238-12.762 months), medium BUB1 expression (8%-28%) (green curve) with a median OS of 25 months (95% CI, 15.555-34.445 months), high expression (>28%) (red curve) with an estimated median survival of 65 months (95% CI, 49.375-80.625 months) (p < 0.001, log-rank test). (D) Two-tier Ki-67 analysis. Low BUB1 expression (<33%) (blue curve) with a median OS of 21 months (95% CI, 12.867-29.133 months), high BUB1 expression (>33%) (green curve) with an estimated median survival of 45 months (95% CI, 22.000-68.000 months) (p = 0.001, log-rank test).