The Complete Loss of p53 Expression Uniquely Predicts Worse Prognosis in Colorectal Cancer

Abstract

p53 immunohistochemistry is considered an accurate surrogate marker reflecting the underlying TP53 mutation status and has utility in tumor diagnostics. In the present study, 269 primary CRCs were immunohistochemically evaluated for p53 expression to assess its utility in diagnostic pathology and prognostication. p53 expression was wild-type in 59 cases (23%), overexpressed in 143 cases (55%), completely lost in 50 cases (19%), and cytoplasmic in 10 cases (4%). p53 immunoreactivity was associated with tumor size (p = 0.0056), mucus production (p = 0.0015), and mismatch repair (MMR) system status (p < 0.0001). Furthermore, among CRCs with wild-type p53 expression, a significantly higher number of cases had decreased CDX2 than those with p53 overexpression (p = 0.012) or complete p53 loss (p = 0.043). In contrast, among CRCs with p53 overexpression, there were significantly fewer ALCAM-positive cases than p53 wild-type cases (p = 0.0045). However, no significant association was detected between p53 immunoreactivity and the “stem-like” immunophenotype defined by CDX2 downregulation and ALCAM-positivity. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio [HR] = 0.17, p < 0.0001), younger age (HR = 0.52, p = 0.021), and female sex (HR = 0.55, p = 0.046) as potential favorable factors. The analysis also revealed complete p53 loss (HR = 2.16, p = 0.0087), incomplete resection (HR = 2.65, p = 0.0068), and peritoneal metastasis (HR = 5.32, p < 0.0001) as potential independent risk factors for patients with CRC. The sub-cohort survival analyses classified according to chemotherapy after surgery revealed that CRC patients with wild-type p53 expression tended to have better survival than those with overexpression or complete loss after chemotherapy. Thus, immunohistochemistry for p53 could be used for the prognostication and chemotherapy target selection of patients with CRC.

Keywords: ALCAM; CDX2; colorectal cancer (CRC); immunohistochemistry; p53; stem-like immunophenotype.

Figure 1

Representative images of p53 immunoreactivity. (a–d), Representative images of p53 immunoreactivity. (a) Wild-type pattern, (b) overexpression, (c) cytoplasmic expression, and (d) complete loss. Arrow heads indicate internal control cells with weak p53 nuclear expression. (e,f), CRC cases with the “stem-like” immunophenotype showing CDX2-negative (e) and ALCAM-positive expression (f). Bar, 50 µm.

Figure 2

Association of p53 immunoreactivity and tumor size. CRCs with wild-type p53 expression showed significantly larger tumors than CRCs with p53 overexpression or complete loss. * p < 0.05; ** p < 0.01.

Figure 3

Cellular proliferation marker expression classified according to p53 expression. (a–d), representative images of immunohistochemistry for cellular proliferation markers. (a) PHH3, (b) CCNA, (c) GMNN, and (d) Ki-67. (e–h) Cellular proliferation marker expression classified by p53 immunoreactivity. (e) PHH3, (f) CCNA, (g) GMNN, and (h) Ki-67. Note that p53-overexpressing tumors contained a significantly higher number of PHH3-positive cells than wild-type tumors. * p < 0.05.

Figure 4

Overall survival of patients with CRC classified according to p53 immunoreactivity. (a) Kaplan–Meier curves for patients classified according to the four p53 expression patterns. CRC patients with complete loss of p53 tended to show worse survival. (b) Kaplan–Meier curves for patients classified into two groups according to p53 immunoreactivity. Note that CRC patients with complete loss of p53 showed significantly worse survival than the group with the other three expression patterns. (c) Kaplan–Meier curves for patients without chemotherapy classified according to four different p53 expression patterns. CRC patients with wild-type p53 expression tended to show worse survival than the others. (d) Kaplan–Meier curves for patients with post-surgery chemotherapy classified according to p53 immunoreactivity. CRC patients with wild-type p53 expression tended to show more favorable survival than the group with p53 overexpression or complete loss.