Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX

Abstract

We evaluated the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in UICC stage III colon cancer by immunohistochemical staining. To identify highfrequency microsatellite instability (MSI þ ) individuals, we performed single-strand conformation polymorphism-based analysis for BAT26. A total of 188 patients who had received 5-fluorouracil (5-FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/ levamisole) were enrolled. Median follow-up was 84.5 months. We found that BAX, Bcl-2 and p53 protein expressions were high or positive in 59, 70 and 50% of 188 cases, respectively. MSI þ tumours were detected in 9% of 174 evaluable patients. BAX or Bcl-2 was correlated with a higher degree of differentiation or left-sided tumours (P ¼ 0.01 or P ¼ 0.03, respectively); MSI was correlated with right-sided tumours (Po0.0001). In contrast to p53, Bcl-2, or MSI, low BAX, advanced pN category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free survival (DFS) (P ¼ 0.0005, P ¼ 0.001, P ¼ 0.005 and P ¼ 0.01, respectively) and poorer overall survival (OS) (P ¼ 0.002, P ¼ 0.0001, P ¼ 0.003 and P ¼ 0.02, respectively). Besides pN category and treatment arm, BAX was an independent variable related to both OS and DFS (P ¼ 0.003 and P ¼ 0.001, respectively). In both univariate and multivariate analysis, the p53À/BAX high in comparison with the p53 þ /BAX high subset conferred a significantly improved DFS (P ¼ 0.03 and P ¼ 0.03, respectively) as well as a marginally improved OS (P ¼ 0.07 and P ¼ 0.08, respectively). BAX protein expression may be of central significance for clinical outcome to 5-FU-based adjuvant chemotherapy in stage III colon cancer, and bivariate analysis of p53/BAX possibly may provide further prognostic evidence.

Analysis of the immunohistochemical expressions of p53, bcl-2 and Ki-67 in colorectal adenocarcinoma and their correlations with the prognostic factors

“…On the other hand, bcl-2 has been correlated with recurrence by some authors, although other studies have shown the same result as in the present study (19,20) . With regard to Ki-67, this study showed a statistically significant correlation between immunohistochemical expression of this protein and recurrence (P = 0.035).…”

“…Among the present study sample, the immunohistochemical expression of bcl-2 was not significantly correlated with the degree of cell differentiation, and this has also been shown in some other studies (2) . On the other hand, a study by Nehls et al (20) showed a statistically significant correlation between bcl-2 and a high degree of cell differentiation. Despite this result, a clear difference was observed between the p53 and bcl-2 expressions, in comparison with tumor expression (85.4% and 31.7%) and degree of cell differentiation (84.6% and 32.1% when evaluating a low degree of differentiation).…”

Disparate clinicopathological correlations of p53 and Bcl-2 in colorectal cancer

“…Such segmental predilection is expected for markers involved in certain steps of the adenoma-carcinoma sequence (7,8,12), the dominant tumorigenic mechanism in CRC (2,22), followed by the large majority of distal tumors. By contrast, a significant part of proximal tumors, evolving through the genetically different microsatellite instability pathway and probably arising from different precursor lesions (serrated polyps) (3,28), usually lacked p53 and Bcl-2 expression (19,27,28). This assumption is also suggested by the reported site-specific prognostic significance of p53 and Bcl-2 (9,13).…”

Köpek Meme Tümörlerinde Bcl-2, Bcl-XL ve Bax Sunulumu İle Apoptotik İndeksin Değerlendirilmesi

“…There are data reporting that overexpression of Bcl-2 is related with down-regulation of Bax and the interruption in the progression of apoptosis is dependent to the imbalance of Bcl-2/Bax, which plays a role in cancer development [15,24,26] . It was reported that in some cancer types such as myeloid leukaemia [27] and cancers of prostate [28] , cervix [19] and colon [29] expression of Bcl-2 is increased. But in previous studies with human breast cancers, it was stated that Bcl-2 expression is generally observed in benign proliferative lesions and small, slowly progressing oestrogen-positive, p53-negative tumours and was found to be related with better prognosis [7,25,30] .…”