title: p53 gene mutations are associated with poor survival in low and low-intermediate risk diffuse large B-cell lymphomas.
abstract: BACKGROUND
  p53 alterations have been associated with a poor prognosis in aggressive B-cell lymphoma. We investigated the clinical relevance of p53 status in diffuse large B-cell lymphoma (DLBCL), focusing on patients who belong to lower risk groups of the international prognostic index and were uniformly treated. We aimed to determine whether this biological marker could identify among such patients those with a pejorative outcome who could benefit from a distinct therapeutic approach.
  
  
  METHODS
  We studied 69 patients presenting with no, one (low-risk, n = 40) or two (low-intermediate risk, n = 29) risk factors treated with an anthracyclin-containing induction regimen. p53 exons 5-8 mutations were screened for using denaturing gradient gel electrophoresis and confirmed by direct sequencing. Immunohistochemical detection of p53 protein and of its downstream target p21 were also evaluated in 60 of 69 cases.
  
  
  RESULTS
  p53 mutations were detected in 16 of 69 (23%) lymphoma samples. The presence of a p53 gene mutation affected survival (P = 0.01), with a 6-year survival rate estimated to be 44% in mutated patients, compared with 79% in non-mutated ones. Using a stepwise Cox model, p53 mutation constituted the only parameter affecting survival (relative risk = 2.7, P = 0.03). A p53+/p21- immunohistochemical pattern (n = 15), suggestive of a disrupted p53 function, strongly correlated with p53 gene status and was associated with a lower 6-year survival rate when compared with a p53(-) or p53+/p21+ phenotype (47% versus 74%, P = 0.05).
  
  
  CONCLUSIONS
  p53 alterations constitute a pejorative biological indicator able to discriminate among clinically defined lower risk patients with DLBCL.
authors.affiliation: Département de Pathologie, Service d'Hématologie and Unité d'Informatique Médicale, Hôpital Henri Mondor, AP-HP, Créteil, France. karen.leroy@hmn.ap-hop-paris.fr
authors.forename: K
authors.initials: K
authors.lastname: Leroy
authors.forename: C
authors.initials: C
authors.lastname: Haioun
authors.forename: E
authors.initials: E
authors.lastname: Lepage
authors.forename: N
authors.initials: N
authors.lastname: Le Métayer
authors.forename: F
authors.initials: F
authors.lastname: Berger
authors.forename: E
authors.initials: E
authors.lastname: Labouyrie
authors.forename: V
authors.initials: V
authors.lastname: Meignin
authors.forename: B
authors.initials: B
authors.lastname: Petit
authors.forename: C
authors.initials: C
authors.lastname: Bastard
authors.forename: G
authors.initials: G
authors.lastname: Salles
authors.forename: C
authors.initials: C
authors.lastname: Gisselbrecht
authors.forename: F
authors.initials: F
authors.lastname: Reyes
authors.forename: Ph
authors.initials: P
authors.lastname: Gaulard
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000032:analysis*; D015331:Cohort Studies; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor