Somatic APC (
adenomatous polyposis coli), TP53, KRAS mutations are present in roughly 80%, 60%, and 40%, respectively, of human
colorectal cancers (
CRCs). Most TP53 mutant alleles in
CRCs encode missense
mutant proteins with loss-of-function (LOF) of p53's transcriptional activity and dominant negative (DN) effects on wild-type p53 function. Missense mutant p53
proteins have been reported to exert gain-of-function (GOF) effects in
cancer. We compared the phenotypic effects of the common human
cancer-associated TP53 R273H missense mutation to p53 null status in a genetically engineered mouse CRC model. Inactivation of one allele of Apc together with activation of a Kras mutant allele in mouse colon epithelium instigated development of serrated and hyperplastic epithelium and
adenomas (AK mice). Addition of a Trp53R270H or Trp53null mutant allele to the model (AKP mice) led to markedly shortened survival and increased
tumor burden relative to that of AK mice, including
adenocarcinomas in AKP mice. Comparable life span and
tumor burden were seen in AKP mice carrying Trp53R270H or Trp53null alleles, along with similar frequencies of spontaneous
metastasis to lymph nodes, lung, and liver. The fraction of
adenocarcinomas with submucosa or deeper invasion was higher in AKP270/fl mice than in AKPfl/fl mice, but the incidence of
adenocarcinomas per mouse did not differ significantly between AKPfl/fl and AKP270/fl mice. In line with their comparable biological behaviors, mouse primary
tumors and
tumor-derived organoids with the Trp53R270H or Trp53null alleles had highly similar gene expression profiles. Human
CRCs with TP53 R273 missense mutant or null alleles also had essentially homogeneous gene expression patterns. Our findings indicate the R270H/R273H p53
mutant protein does not manifest definite GOF biological effects in mouse and human
CRCs, suggesting possible GOF effects of mutant p53 in
cancer phenotypes are likely allele-specific and/or context-dependent.