title: Effect of the codon 72 polymorphism (c.215G>C, p.Arg72Pro) in combination with somatic sequence variants in the TP53 gene on survival in patients with advanced ovarian carcinoma.
abstract: This study was conducted to evaluate the frequency and prognostic impact of TP53 alterations stratified for the TP53 codon 72 polymorphism (c.215G>C, p.Arg72Pro) in a cohort of 109 patients with advanced ovarian carcinomas. TP53 sequence variants were observed in 80 of the 109 (73.4%) tumors and were significantly associated with grade of differentiation (P=0.001). A tendency towards higher frequency of sequence variants in tumors with higher FIGO stages was seen (P=0.05). The type of TP53 sequence variant (transition A:T>G:C vs. G:C>A:T at CpG dinucleotides, and transversion G:C>T:A) had significant correlation with patients' age (P=0.04) with more A:T>G:C in patients over 60 years old. No significant associations were found between frequency of sequence variants and age at diagnosis, histological type, size of residual tumor after primary surgery, or long-term survival. Analyses of the codon 72 polymorphism in tumor DNA gave a higher frequency of homozygosity/hemizygosity than expected from the population frequency, particularly for the Pro allele. Tumors homozygous or hemizygous for the Pro allele had significantly higher frequency of TP53 sequence variants, particularly of the nonmissense type (P=0.002), and patients with these types of alterations had significantly shorter survival (P=0.04). TP53 protein accumulation, determined by immunohistochemistry (IHC), was found in 67.9% (74 out of 109) of the tumors, was significantly more common among serous than nonserous ovarian carcinomas (P=0.008), and had a significant effect on progression-free survival (P=0.03). p63 (TP73L; formerly TP63) and p73 (TP73) protein accumulation detected by IHC was seen in 67.9 and 0% of the tumors, respectively. A significantly higher frequency of p63-positive cases was seen among serous tumors (P=0.008) and tended to increase with increasing FIGO stages (P=0.05), but had no significant effect on survival. No association between p63 protein accumulation and TP53 protein accumulation was seen.
authors.affiliation: Department of Gynecologic Oncology, The Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Pedro
authors.initials: P
authors.lastname: Kringen
authors.forename: Gunnar B
authors.initials: GB
authors.lastname: Kristensen
authors.forename: Ruth
authors.initials: R
authors.lastname: Holm
authors.forename: Mark M O
authors.initials: MM
authors.lastname: Baekelandt
authors.forename: Magali
authors.initials: M
authors.lastname: Olivier
authors.forename: Hanne
authors.initials: H
authors.lastname: Skomedal
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.forename: Claes G
authors.initials: CG
authors.lastname: Tropé
authors.forename: Vera M
authors.initials: VM
authors.lastname: Abeler
authors.forename: Jahn M
authors.initials: JM
authors.lastname: Nesland
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Aslaug
authors.initials: A
authors.lastname: Helland
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution / Q000235:genetics; D001120:Arginine / Q000235:genetics*; D003062:Codon / Q000235:genetics*; D015331:Cohort Studies; D003596:Cytosine / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D016147:Genes, Tumor Suppressor; D016158:Genes, p53 / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006147:Guanine / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D011392:Proline / Q000235:genetics*; D016019:Survival Analysis; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D006147:Guanine; D003596:Cytosine; D001120:Arginine; D011392:Proline