title: Distinctive patterns of p53 protein expression and microsatellite instability in human colorectal cancer.
abstract: Although evidence suggests an inverse relationship between microsatellite instability and p53 alterations in colorectal cancer, no study has thoroughly examined the use of p53 immunohistochemistry in phenotyping colorectal cancers. We investigated the value of p53 immunohistochemistry in microsatellite instability-positive colorectal cancers prescreening and attempted to clarify the relationship between DNA mismatch repair system and p53 pathway. In a series of 104 consecutive colorectal cancers, we performed p53 immunohistochemistry, TP53 mutational analysis, DNA mismatch repair system efficiency evaluation (DNA mismatch repair system immunohistochemistry, microsatellite instability status, MLH1/MSH2 germ line, and BRAF, murine double minute 2, and p21 immunohistochemistry. Microsatellite instability high was observed in 25 of 104 colorectal cancers, with DNA mismatch repair system protein loss (24/25) and germ line (8/25) or BRAF mutations (8/25). p53 immunohistochemistry revealed 3 distinct patterns of expression: complete negative immunostaining associated with truncating TP53 mutations (P < .0001), diffuse overexpression associated with missense TP53 mutations (P < .0001), and restricted overexpression characterized by a limited number of homogenously scattered strongly positive tumor cells in 36.5% of colorectal cancers. This latest pattern was associated with wild-type TP53 and microsatellite instability high colorectal cancers (P < .0001) including all Lynch tumors (8/8), but its presence among 22% of DNA mismatch repair system-competent colorectal cancers decreased its positive predictive value (55.2% [95% confidence interval, 45%-65%]). It was also correlated with murine double minute 2 overexpression (P < .0001) and inversely with p21 loss (P = .0002), independently of microsatellite instability status. In conclusion, a restricted pattern of p53 overexpression is preferentially associated with microsatellite instability high phenotype and could, therefore, be of clinical use as signal for microsatellite instability analysis in a large-scale tumor screening. Its association with concomitant murine double minute 2 overexpression suggests an alternative mechanism of p53 pathway deregulation.
authors.affiliation: Center for Human Genetics, School of Medicine, Université Catholique de Louvain, Cliniques universitaires Saint-Luc, B-1200 Brussels, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Nyiraneza
authors.forename: Anne
authors.initials: A
authors.lastname: Jouret-Mourin
authors.forename: Alex
authors.initials: A
authors.lastname: Kartheuser
authors.forename: Philippe
authors.initials: P
authors.lastname: Camby
authors.forename: Olivier
authors.initials: O
authors.lastname: Plomteux
authors.forename: Roger
authors.initials: R
authors.lastname: Detry
authors.forename: Karin
authors.initials: K
authors.lastname: Dahan
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D016001:Confidence Intervals; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D051379:Mice; D053842:Microsatellite Instability; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011237:Predictive Value of Tests; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf