TP53 mutation in colorectal cancer

Abstract

For the p53 Special IssueApproximately half of all colorectal cancers show p53 (TP53) gene mutations, with higher frequencies observed in distal colon and rectal tumors and lower frequencies in proximal tumors and those with the microsatellite instability or methylator phenotypes. Alterations to this gene appear to have little or no prognostic value for colorectal cancer patients treated by surgery alone, but are associated with worse survival for patients treated with chemotherapy. There is some evidence that different p53 mutations are associated with different clinical features including prognosis and response to therapy, although further large studies are required to confirm this. Several in vitro, animal and clinical studies have shown that normal p53 is required for the response of colorectal cancers to 5-fluorouracil-based chemotherapy. This should be confirmed by additional retrospective cohort studies and by the incorporation of P53 status in ongoing and future clinical trials. The evaluation of p53 overexpression, using a standardized immunohistochemical (IHC) procedure, could be a clinically useful marker for the identification of colorectal cancer patients likely to benefit from the standard chemotherapy regime currently used for this disease. Hum Mutat 21:271-276,

Maximum likelihood analysis of mammalian p53 indicates the presence of positively selected sites and higher tumorigenic mutations in purifying sites

“…The rate of transition and transversion also varies among different cancer. For example, in colon cancer the rate of transition at CpG dinucleotides is higher, whereas in lung cancer the rate of transversion is higher (Iacopetta, 2003).…”

“…Divided over tissues, statistical data show that occurrence of p53 mutations is most prevalent in lung (70%), colon (60%), stomach (45%) and breast (20%) cancer (Fenoglio-Preiser et al, 2003;Gasco et al, 2003;Iacopetta, 2003;Toyooka et al, 2003). Inactivation of the p53 gene occurs due to missense and nonsense mutations or insertions/deletions of several nucleotides, which leads to either expression of mutant protein or absence of protein (Benard et al, 2003).…”

Crippling p53 activities via knock-in mutations in mouse models

“…In vitro and in vivo studies show that some mutant p53 proteins have oncogenic potential, called gain of function (Roemer, 1999;Deppert et al, 2000;van Oijen and Slootweg, 2000;Cadwell and Zambetti, 2001). Clinically, patients with some p53 missense mutations have a worse prognosis than patients with deletion of p53, supporting the gainof-function hypothesis (Roemer, 1999;Lai et al, 2000;Powell et al, 2000;Skaug et al, 2000;Iacopetta, 2003). To address mechanisms of gain of function in vivo, two groups have recently characterized knock-in mice with p53 'hot spot' missense mutations Olive et al, 2004).…”

Activity (transcription) of the genes for MLH1, MSH2 and p53 in sporadic colorectal tumours with micro-satellite instability

“…Direct sequencing and SSCP also have their limitations in detecting p53 mutations. With direct DNA sequencing, contamination from normal DNA can mask the true result of tumour DNA analysis, and although SSCP has been widely used for screening mutations these have been mainly in exons 5 -8 of p53 (Iacopetta, 2003), but not other regions. In our samples, a reduced rate of p53 transcription to a level below that in normal bowel might explain the reduced p53 function in these cancers.…”