title: p53 mutations in L3-loop zinc-binding domain, DNA-ploidy, and S phase fraction are independent prognostic indicators in colorectal cancer: a prospective study with a five-year follow-up.
abstract: p53 gene alterations are among the most common events observed in colorectal cancer,and are accompanied frequently by DNA aneuploidy and high proliferative activity. The prognostic significance of such mutations remains controversial. We prospectively evaluated the prognostic significance of p53 mutations, DNA-ploidy, and S phase fraction (SPF) in a consecutive series of 160 colorectal cancer patients (median follow-up 71 months). Tumor DNA was screened for p53 mutations by PCR/single-strand conformational polymorphism/sequencing. DNA-ploidy and SPF were assessed by DNA flow cytometry. p53 mutations were detected in 68 of 160 (42.5%) cases. In 56% (38 of 68) of these, p53 mutations were found in conserved areas of the gene and in 44% (30 of 68 cases) outside the conserved regions. Eighteen of the 68 cases (26%) had mutations in the L3 loop, 11 of 68 (16%) in the L1 loop-sheet-alpha helix motif, and 39 of 68 (58%) outside L3 and loop-sheet-alpha helix. Seventy-five percent of the cases (120 of 160) showed DNA aneuploidy, whereas 18% of these (22 of 120) were multiclonal. The major independent predictors for both disease relapse and death were advanced Dukes' stage, p53 mutations affecting L3 loop, DNA-aneuploid tumors, and high SPF (>18.5%). Our results show that mutations in L3 functional domain, more than any mutations, are important biological indicators to predict the outcome of patients indicating that these mutations have biological relevance in terms of colorectal cancer disease course.
authors.affiliation: Section of Molecular Oncology, Department of Oncology, Regional Reference Center for the Biomolecular Characterization of Neoplasms and Genetic Screening of Hereditary Tumors, Palermo, Italy. Lab-oncobiologia@usa.net
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.forename: Manuela
authors.initials: M
authors.lastname: Migliavacca
authors.forename: Ines
authors.initials: I
authors.lastname: Zanna
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Valerio
authors.forename: Mario Adelfio
authors.initials: MA
authors.lastname: Latteri
authors.forename: Nello
authors.initials: N
authors.lastname: Grassi
authors.forename: Gianni
authors.initials: G
authors.lastname: Pantuso
authors.forename: Sergio
authors.initials: S
authors.lastname: Salerno
authors.forename: Gabriella
authors.initials: G
authors.lastname: Dardanoni
authors.forename: Ida
authors.initials: I
authors.lastname: Albanese
authors.forename: Mario
authors.initials: M
authors.lastname: La Farina
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Tomasino
authors.forename: Nicola
authors.initials: N
authors.lastname: Gebbia
authors.forename: Viviana
authors.initials: V
authors.lastname: Bazan
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D003062:Codon / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D004273:DNA, Neoplasm / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D011003:Ploidies; D011110:Polymorphism, Genetic / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D017434:Protein Structure, Tertiary / Q000235:genetics; D016196:S Phase / Q000235:genetics; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D003062:Codon; D004273:DNA, Neoplasm; C017800:zinc-binding protein