p53 in colorectal cancer: clinicopathological correlation and prognostic significance

Abstract

Summary p53 protein was detected by immunohistochemistry in 42% of 52 colorectal adenocarcinomas. Positive tumours were significantly more frequent in the distal colon, and demonstrated a higher rate of cell proliferation. No correlation was found with tumour grade, Dukes' stage, presence of DNA aneuploidy or patient survival. The role of p53 in colorectal carcinogenesis is discussed with particular reference to differences between proximal and distal large bowel cancers. p53 is a 53kD nuclear protein, highly conserved in vertebrates, which is believed to regulate entry into and progression through the normal cell cycle (Mercer et al., 1984). Like c-myc it is induced during transition from Go to G, phase (Milner & Milner, 1981;Reich & Levine, 1984), and is present at low levels in most normal fetal and adult tissues (Rogel et al., 1985). Studies of p53 expression in cultured cells suggest that increased levels are associated either with an abnormal mutated protein (Finlay et al., 1988), or stablisation of the protein in a complex with viral antigens, e.g. SV40 large T antigen (Lane & Crawford, 1979). Point mutations occurring in a highly conserved region of the gene are known to activate p53 in the primary rat embryo fibroblast transfection assay for dominant oncogenes , whereas the wild type protein has a tumour suppressor action . The presence of increased levels of protein may therefore provide a marker for mutated p53.Elevated p53 expression has been described in a number of human tumours including carcinoma of the breast (Crawford et al., 1984;Cattoretti et al., 1988;Thompson et al., 1990), colorectum (Crawford et al., 1984), and lung (Iggo et al., 1990). Colorectal cancer is characterised by frequent deletion of chromosome 17p close to the p53 locus (Vogelstein et al., 1988), and elevated protein levels have been found by radioimmunoassay in 44% of tumours (Crawford et al., 1984). These studies suggest that in some tumours hemizygous deletion of one p53 allele is accompanied by mutation and overexpression of the other. Recently van den Berg et al. (1989) described the immunohistochemical detection of p53 in 55% of 29 colorectal cancers. However no information was given regarding the relationship of p53 expression to clinico-pathological variables several of which are believed to correlate with the biological aggressiveness and stage of progression of a tumour. The aim of the present study was to assess these relationships in a larger series and investigate the value of the immunocytochemical detection of p53 as a prognostic indicator. Materials and methodsFresh tumour tissue was obtained from 52 adenocarcinomas of the large bowel from 52 patients. A single 4 p frozen section was cut from each tumour, air dried overnight, and fixed for 15 min in acetone at 4'C.In five cases tissue was available from up to five different areas of the same tumour. These were included in the main series in order to assess the effect of intra-tumour heterogeneity on the detection of p53.Sections were incubated with Pab421, ...

hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer

“…17 We could also demonstrate a significant correlation between increased hTERT gene copy number and aneuploidy. The relationship in colorectal cancer between p53 abnormalities and aneuploidy is well known 30,31 and aneuploidy and gene amplification is closely related. 27 Furthermore, inactivation of p53 has been suggested as a requirement for admitting gene amplification.…”

Prognostic significance of p53 overexpression in gastric and colorectal carcinoma

“…They suggested that evaluating p53 expression may prove useful in determining different biological subgroups of colorectal cancer. However, in a later study of 52 colorectal carcinomas (Scott et al, 1991) Campo et al (1991) demonstrated that right sided tumours were less p53 immunoreactive than distal carcinomas and did not find a correlation between p53 expression and tumour differentiation. Our data are also consistent with recent studies on breast cancer which also reported a prognostic significance of p53 overexpression.…”

“…Statistical analysis of follow-up data of 47 patients with gastric carcinoma (20 with p53 positive and 27 with p53 negative tumours) and of 80 patients operated on for colorectal cancer (36 with p53 positive and 44 with p53 negative tumours), revealed that p53 overexpression in both carcinomas is significantly associated with early relapse and death (P<0.001). Thus,18 (Crawford et al, 1984;Remvikos et al, 1990;Rodrigues et al, 1990;Scott et al, 1991;Campo et al, 1991 (Fielding & Priestman, 1986;Preece et al, 1986). The prognosis is worse for cancers which originate in the upper third of stomach or in the rectum.…”

“…Recently Scott et al (1991) and Campo et al (1991) (Cattoretti et al, 1988) and tumour stage (Davidoff et al, 1991a,b).…”

Overexpression of p53 and long-term survival in colon carcinoma

“…Most forms of mutations result in the formation of an abnormal protein with novel oncogenic properties and prolonged half-life (Finlay et al, 1988). The accumulation of such mutated protein in the tumour cell nuclei can be detected by immunohistochemical staining (Scott et al, 1991). This does not apply to frameshift and chain-terminating (nonsense) mutations, which do not result in elevated p53 protein content.…”