Have p53 gene mutations and protein expression a different biological significance in colorectal cancer?*

Abstract

p53 alterations are considered the most common genetic events in many types of neoplasms, including colorectal carcinoma (CRC). These alterations include mutations of the gene and/or overexpression of the protein. The aim of our study was to assess whether in 160 patients undergoing resective surgery for primary operable CRC there was an association between p53 mutations and protein overexpression and between these and other biological variables, such as cell DNA content (DNA-ploidy) and S-phase fraction (SPF), and the traditional clinicopathological variables. p53 mutations, identified by PCR-SSCP-sequencing analysis, were found in 68/160 patients (43%) and positive staining for p53 protein, detected with the monoclonal antibody DO-7, was present in 48% (77/160) of the cases, with agreement of 57% (91/160). In particular, a significant association was found between increased p53 expression and genetic alterations localized in the conserved regions of the gene or in the L3 DNA-binding domain and the specific type of mutation. Furthermore, both overexpression of p53 and mutations in the conserved areas of the gene were found more frequently in distal than in proximal CRCs, suggesting that they might be ''biologically different diseases.'' Although p53 mutations in conserved areas were associated with flow cytometric variables, overexpression of p53 and mutations in its L3 domain were only related respectively to DNA-aneuploidy and high SPF. These data may reflect the complex involvement of p53 in the different pathways regulating cell-cycle progression. In conclusion, the combination of the mutational status and immunohistochemistry of p53, and flow cytometric data may provide an important insight into the biological features of CRCs.

CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

“…40,41 Furthermore, it is known that accumulation of the nonmutated protein can occur due to the formation of complexes between p53 and other cellular proteins such as MDM2 or viral proteins such as the viral oncoprotein E6. 42 In conclusion, positive p53 stainings are not synonymous with TP53 mutations.…”

P53 abnormalities and outcomes in colorectal cancer: a systematic review

“…There is, to judge by usage, no consensus on any optimal method for the use of IHC to detect abnormal accumulation of p53; nor is there any apparent agreement on how best to identify mutations in the 11 exons of the p53 gene. Given that mutation and accumulation, as detected by IHC, may be telling us different things (Bazan et al, 2002), it would be sensible if future studies combined both methods of assessment. Until procedures and approaches to the investigation of p53 status are standardised, there can be no real progress: Dix millions d'ignorances, ne font pas un savoir (Ten million errors do not leave us any the wiser; Hippolyte Taine, 1823 -1898).…”

Determination of Molecular Marker Expression Can Predict Clinical Outcome in Colon Carcinomas

“…The study population consisted of 104 consecutive patients (73 male, 31 female; age range, 28 -84 years; mean 63.8 Ϯ 11.9 years) observed between January 1995 and December 2000, with histologically proven colon carcinoma. Patients meeting the Amsterdam II criteria for hereditary nonpolyposis CRC syndrome or with carcinomas associated with inflammatory bowel disease or with rectal cancers were not considered suitable for this study because their molecular features, recurrence rate, and overall survival can differ greatly from sporadic large bowel carcinomas, thus possibly causing misinterpretation of the results (15,28). Twenty-five subjects without colon carcinoma undergoing endoscopic biopsy of normal-appearing colon mucosa served as controls.…”