title: Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.
abstract: BACKGROUND
  Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity.
  
  
  METHODS
  TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation.
  
  
  RESULTS
  Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability.
  
  
  CONCLUSIONS
  Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.
authors.affiliation: Università di Palermo, Department of Oncology, Palermo, Italy. bjiac@meddent.uwa.edu.au
authors.forename: B
authors.initials: B
authors.lastname: Iacopetta
authors.forename: A
authors.initials: A
authors.lastname: Russo
authors.forename: V
authors.initials: V
authors.lastname: Bazan
authors.forename: G
authors.initials: G
authors.lastname: Dardanoni
authors.forename: N
authors.initials: N
authors.lastname: Gebbia
authors.forename: T
authors.initials: T
authors.lastname: Soussi
authors.forename: D
authors.initials: D
authors.lastname: Kerr
authors.forename: H
authors.initials: H
authors.lastname: Elsaleh
authors.forename: R
authors.initials: R
authors.lastname: Soong
authors.forename: D
authors.initials: D
authors.lastname: Kandioler
authors.forename: E
authors.initials: E
authors.lastname: Janschek
authors.forename: S
authors.initials: S
authors.lastname: Kappel
authors.forename: M
authors.initials: M
authors.lastname: Lung
authors.forename: C-S S
authors.initials: CS
authors.lastname: Leung
authors.forename: J M
authors.initials: JM
authors.lastname: Ko
authors.forename: S
authors.initials: S
authors.lastname: Yuen
authors.forename: J
authors.initials: J
authors.lastname: Ho
authors.forename: S Y
authors.initials: SY
authors.lastname: Leung
authors.forename: E
authors.initials: E
authors.lastname: Crapez
authors.forename: J
authors.initials: J
authors.lastname: Duffour
authors.forename: M
authors.initials: M
authors.lastname: Ychou
authors.forename: D T
authors.initials: DT
authors.lastname: Leahy
authors.forename: D P
authors.initials: DP
authors.lastname: O'Donoghue
authors.forename: V
authors.initials: V
authors.lastname: Agnese
authors.forename: S
authors.initials: S
authors.lastname: Cascio
authors.forename: G
authors.initials: G
authors.lastname: Di Fede
authors.forename: L
authors.initials: L
authors.lastname: Chieco-Bianchi
authors.forename: R
authors.initials: R
authors.lastname: Bertorelle
authors.forename: C
authors.initials: C
authors.lastname: Belluco
authors.forename: W
authors.initials: W
authors.lastname: Giaretti
authors.forename: P
authors.initials: P
authors.lastname: Castagnola
authors.forename: E
authors.initials: E
authors.lastname: Ricevuto
authors.forename: C
authors.initials: C
authors.lastname: Ficorella
authors.forename: S
authors.initials: S
authors.lastname: Bosari
authors.forename: C D
authors.initials: CD
authors.lastname: Arizzi
authors.forename: M
authors.initials: M
authors.lastname: Miyaki
authors.forename: M
authors.initials: M
authors.lastname: Onda
authors.forename: E
authors.initials: E
authors.lastname: Kampman
authors.forename: B
authors.initials: B
authors.lastname: Diergaarde
authors.forename: J
authors.initials: J
authors.lastname: Royds
authors.forename: R A
authors.initials: RA
authors.lastname: Lothe
authors.forename: C B
authors.initials: CB
authors.lastname: Diep
authors.forename: G I
authors.initials: GI
authors.lastname: Meling
authors.forename: J
authors.initials: J
authors.lastname: Ostrowski
authors.forename: L
authors.initials: L
authors.lastname: Trzeciak
authors.forename: K
authors.initials: K
authors.lastname: Guzinska-Ustymowicz
authors.forename: B
authors.initials: B
authors.lastname: Zalewski
authors.forename: G M
authors.initials: GM
authors.lastname: Capellá
authors.forename: V
authors.initials: V
authors.lastname: Moreno
authors.forename: M A
authors.initials: MA
authors.lastname: Peinado
authors.forename: C
authors.initials: C
authors.lastname: Lönnroth
authors.forename: K
authors.initials: K
authors.lastname: Lundholm
authors.forename: X F
authors.initials: XF
authors.lastname: Sun
authors.forename: A
authors.initials: A
authors.lastname: Jansson
authors.forename: H
authors.initials: H
authors.lastname: Bouzourene
authors.forename: L-L
authors.initials: LL
authors.lastname: Hsieh
authors.forename: R
authors.initials: R
authors.lastname: Tang
authors.forename: D R
authors.initials: DR
authors.lastname: Smith
authors.forename: T G
authors.initials: TG
authors.lastname: Allen-Mersh
authors.forename: Z A J
authors.initials: ZA
authors.lastname: Khan
authors.forename: A J
authors.initials: AJ
authors.lastname: Shorthouse
authors.forename: M L
authors.initials: ML
authors.lastname: Silverman
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.forename: C
authors.initials: C
authors.lastname: Ishioka
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007390:International Agencies; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53