Physical inactivity, large body mass index, cigarette smoking, using aspirin/nonsteroidal anti-inflammatory drugs, and other dietary factors appeared to be comparably associated with colon cancer in those with and without p53 mutations.
To demonstrate the program, the mutational spectra of single base substitutions in the p53 gene are compared in (i) bladder cancers from smokers and non-smokers, (ii) small-cell lung cancers, non-small-cell lung cancers and colon cancers and (iii) hepatocellular carcinomas from high- and low-aflatoxin exposure groups. p53 mutations differ in several important aspects from a typical mutational spectra experiment, where a homogeneous population of cells is treated with a specific mutagen and mutations at a specific locus are recovered by phenotypic selection.
The second form of genetic instability is characterized by the development of p53 gene abnormalities that result in gross aneuploidy and multiple structural chromosomal changes. p53/aneuploidy affects most colon cancers, breast cancers, and many other solid tumors.
In the present study, a large family with evidence of polyposis and colon cancer was screened for the mutations of the p53 gene and protein overexpression.
Human colon cancer development is associated with the accumulation of mutations and deletions in the suppressor genes DCC, APC and p53 and mutations in the dominant oncogene K-ras, with loss of wild type alleles.
This was confirmed by logistic regression, as the GSTT1 null polymorphism in combination with either the TP53 or the CASP8 polymorphism significantly alter colon cancer risk (p(interaction) < 0.02 for both).
Simple staining for beta-galactosidase allowed us to confirm that the colon cancer cell lines LIM1215 and HCT116, as well as the breast cancer cell line MCF7. have wild-type p53, and the colon cancer cell line Caco-2 as well as breast cancer cell lines MDA-MB-435 and MDA-MB-231 have mutant p53.
Mechanistic studies were performed in two each of p53 wild-type (HCT116, LoVo) and p53-mutated (SW480, HT29) colon cancer cells to explore whether LKB1 loss could be deregulated by NKX2-1-mediated p53 pathway.
In a series of 11 microsatellite stable (MSS) and 9 microsatellite unstable (MSI) colon cancer cell lines and primary colon carcinomas (25 MSS and 28 MSI) with known ploidy stem line and APC, KRAS, and TP53 mutation status, we analyzed the promoter methylation of the following genes: hMLH1, MGMT, p16INK4a (CDKN2A alpha-transcript), p14ARF (CDKN2A beta-transcript), APC, and E-cadherin (CDH1).
Unexpectedly, RER colon cancers bearing mutant p53 demonstrated the same stability of chromosome number, and the same stability of chromosome structure, as the RER colon cancers with wild-type p53.
Mutational analyses revealed that a single point mutation in p53 (K382R) abolished its capacity to inhibit autophagy upon transfection into p53-deficient human colon cancer or yeast cells.
Data analysis comparing colon cancer entries in the TP53 database (http://p53.curie.fr) with the results reported in this study showed that distribution of mutations and the mutational events were comparable.
Differential GADD45, p21CIP1/WAF1, MCL-1 and topoisomerase II gene induction and secondary DNA fragmentation after camptothecin-induced DNA damage in two mutant p53 human colon cancer cell lines.
The synthetic glucocorticoid dexamethasone elevated KILLER/DR5 mRNA in glioblastoma, ovarian cancer, and colon cancer cell lines with mutant p53 undergoing apoptosis, and this induction was inhibited by the transcriptional inhibitor actinomycin D. Although another glucocorticoid, prednisolone, also induced apoptosis, it did not increase KILLER/DR5 mRNA.
The correlation between p53 mutations and the histological status of the samples suggest the involvement of this genetic event in the development of colon cancer in patients with ulcerative colitis.