Prognostic Value of the Expression of DNA Repair-Related Biomarkers Mediated by Alcohol in Gastric Cancer Patients

Abstract

Alcohol consumption likely induces gastric carcinogenesis through deregulation of RNA polymerase (Pol) III genes and oxidative damage. Transcription factor IIB-related factor 1 (BRF1) overexpression alleviates RNA Pol III transcription inhibition through breast cancer susceptibility gene 1 (BRCA1). Myeloperoxidase (MPO) involvement in cancer is induced by alcohol-mediated oxidative damage. BRCA1/2 and MPO play key roles in DNA repair. BRCA1 and BRCA2 exert different roles in homologous recombination repair. By using human gastric cancer (GC) biopsies, we investigated the prognostic value of these proteins upon alcohol induction. In total, high expression of BRF1 (P = 0.010) and positive cell infiltration of MPO (P = 0.004) in tumor tissues as well as positive expression of BRCA1 (P < 0.001) in para-tumor tissues were more frequent in GC patients with hazardous or harmful alcohol consumption habits. BRF1 (P = 0.021), BRCA2 (P < 0.001), and MPO (P = 0.039) were independent prognostic factors for disease-free survival. BRCA1 (P = 0.005) and BRCA2 (P < 0.001) also were identified as independent prognostic factors for overall survival. Furthermore, BRCA2 was an independent unfavorable prognostic factor for disease-free survival and overall survival (P < 0.001) in GC patients who underwent platinum-based adjuvant chemotherapy. BRF1, BRCA1/2, and MPO are DNA repair-related biomarkers, induced by alcohol with prognostic value in GC patients.

Figure 1

Immunohistochemical staining of BRF1 in gastric cancer (GC). A and B: High transcription factor II B–related factor 1 (BRF1) expression in GC tissue. C: Positive BRF1 expression in GC para-tumor tissue. D and E: Low BRF1 expression in GC tissue. F: Negative BRF1 expression in GC para-tumor tissue. Original magnification: ×100 (A and D); ×400 (B, C, E, and F).

Figure 2

Immunohistochemical staining of BRCA2 in gastric cancer (GC). A and B: Positive BRCA2 expression in GC tissue. C: Positive BRCA2 expression in GC para-tumor tissue. D and E: Negative BRCA2 expression in GC tissue. F: Negative BRCA2 expression in GC para-tumor tissue. Original magnification: ×100 (A and D); ×200 (C and F); ×400 (B and E).

Figure 3

Immunohistochemical staining of BRCA1 in gastric cancer (GC). A and B: Positive BRCA1 expression in GC tissue. C: Positive BRCA1 expression in GC para-tumor tissue. D and E: Negative BRCA1 expression in GC tissue. F: Negative BRCA1 expression in GC para-tumor tissue. Original magnification: ×100 (A and D); ×400 (B, C, E, and F).

Figure 4

Immunohistochemical staining of myeloperoxidase (MPO) in gastric cancer (GC). A–C: MPO-positive inflammatory cell infiltration is discovered in GC (A and B) tissues and para-tumor tissue (C). D and E: Absence of MPO-positive inflammatory cell infiltration in GC tissue. F: Absence of MPO-positive inflammatory cell infiltration in GC para-tumor tissue. Original magnification: ×100 (A and D); ×400 (B, C, E, and F).

Figure 5

A: Histochemical scores (H-scores) for the four biomarkers in gastric cancer (GC) tissues (dark gray) are higher than those in GC para-tumor tissues (light gray) (P < 0.001). B: High transcription factor II B–related factor 1 (BRF1) (P = 0.010) expression and myeloperoxidase (MPO)-positive (P = 0.004) cell infiltration are more frequent in GC patients with hazardous or harmful alcohol consumption habits. C and D: There is a statistically significant correlation between the H-scores for BRCA1/2 in tumor tissues (r = 0.696, P < 0.001; C) and para-tumor tissues (r = 0.715, P < 0.001; D) in GC patients.

Figure 6

A: Co-localization of BRF1 and BRCA1 in tumor cell nuclei in gastric cancer (GC). B: Transcription factor II B–related factor 1 (BRF1) is located in the tumor cell nucleus and cytoplasm. C: BRCA1 was stained in the tumor cell nucleus. D: DAPI. Scale bars: 25 μm.

Figure 7

Kaplan-Meier survival analysis for transcription factor II B–related factor 1 (BRF1) (A and E), BRCA1 (B and F), and BRCA2 expression (C and G), and myeloperoxidase (MPO)-positive cell infiltration (D and H). Patients with high BRF1 (P = 0.003; A)/BRCA1 (P = 0.005; B)/BRCA2 (P < 0.001; C) expression and MPO-positive cell infiltration (P = 0.013; D) show a shorter disease-free survival (DFS), and patients with high BRF1 (P = 0.006; E)/BRCA1 (P < 0.001; F)/BRCA2 (P < 0.001; G) expression and MPO-positive cell infiltration (P = 0.034; H) show a worse overall survival (OS).

Figure 8

Kaplan-Meier survival analysis for BRCA1 (A and D) and BRCA2 expression (B and E), and myeloperoxidase (MPO)-positive cell infiltration (C and F). Patients who received platinum-based adjuvant chemotherapy and showed negative or low BRCA1/2 expression showed significantly longer disease-free survival (DFS) (BRCA1: P = 0.010, A; BRCA2: P < 0.001, B) and overall survival (OS) (BRCA1: P = 0.003, D; BRCA2: P < 0.001, E).