title: The prognostic significance of the aberrant extremes of p53 immunophenotypes in breast cancer.
abstract: OBJECTIVE
  The utility of p53 as a prognostic assay has been elusive. The aims of this study were to describe a novel, reproducible scoring system and assess the relationship between differential p53 immunohistochemistry (IHC) expression patterns, TP53 mutation status and patient outcomes in breast cancer.
  
  
  RESULTS
  Tissue microarrays were used to study p53 IHC expression patterns: expression was defined as extreme positive (EP), extreme negative (EN), and non-extreme (NE; intermediate patterns). Overall survival (OS) was used to define patient outcome. A representative subgroup (n = 30) showing the various p53 immunophenotypes was analysed for TP53 hotspot mutation status (exons 4-9). Extreme expression of any type occurred in 176 of 288 (61%) cases. As compared with NE expression, EP expression was significantly associated (P = 0.039) with poorer OS. In addition, as compared with NE expression, EN expression was associated (P = 0.059) with poorer OS. Combining cases showing either EP or EN expression better predicted OS than either pattern alone (P = 0.028). This combination immunophenotype was significant in univariate but not multivariate analysis. In subgroup analysis, six substitution exon mutations were detected, all corresponding to extreme IHC phenotypes. Five missense mutations corresponded to EP staining, and the nonsense mutation corresponded to EN staining. No mutations were detected in the NE group.
  
  
  CONCLUSIONS
  Patients with extreme p53 IHC expression have a worse OS than those with NE expression. Accounting for EN as well as EP expression improves the prognostic impact. Extreme expression positively correlates with nodal stage and histological grade, and negatively with hormone receptor status. Extreme expression may relate to specific mutational status.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Boyle
authors.forename: Darragh G
authors.initials: DG
authors.lastname: McArt
authors.forename: Gareth
authors.initials: G
authors.lastname: Irwin
authors.forename: Charlotte S
authors.initials: CS
authors.lastname: Wilhelm-Benartzi
authors.forename: Tong F
authors.initials: TF
authors.lastname: Lioe
authors.forename: Elena
authors.initials: E
authors.lastname: Sebastian
authors.forename: Stephen
authors.initials: S
authors.lastname: McQuaid
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hamilton
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: James
authors.forename: Paul B
authors.initials: PB
authors.lastname: Mullan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Catherwood
authors.forename: D Paul
authors.initials: DP
authors.lastname: Harkin
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping / Q000379:methods; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015203:Reproducibility of Results; D012189:Retrospective Studies; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C508053:ERBB2 protein, human
keywords: breast cancer; immunohistochemistry; mutation; p53 protein; prognosis