title: Bcl-6 p53 mutations in lymphomas carrying the bcl-2/Jh rearrangement.
abstract: OBJECTIVE
  The t(14;18)(q32;q21) chromosomal translocation is the hallmark of follicular lymphomas (FL). The translocation induces the overexpression of the Bcl-2 protein and prolongs the survival of clonogenic cells. Tumor cells may acquire additional molecular alterations that may be associated with histologic progression or with chemo-resistance.
  
  
  METHODS
  We analyzed the distribution and association of bcl-6 and p53 mutations in 55 consecutive bcl-2/Jh+ lymphoma samples derived from 43 patients obtained at the time of diagnosis and, in 5 of these patients, during follow-up. A total of 29 bcl-6 point mutations were detected in seventeen patients (40%) associated with major or minor breakpoints of the bcl-2/Jh fusion gene. In seven cases a p53 mutation was detected. Three cases corresponded to FL with the minor breakpoint in the bcl-2 gene and these patients had a favorable clinical evolution, whereas the 4 patients with p53 mutations and the major breakpoint had a bad clinical outcome with morphologic transformation to high-grade lymphoma in three cases. The sequential analysis of 5 patients showed a different timing in the acquisition of mutations: one patient showed bcl-6 and p53 mutations at diagnosis, another patient showed bcl-6 mutations at diagnosis and acquired a p53 mutation later whereas the third patient had a p53 mutation before the appearance of the bcl-6 mutation.
  
  
  RESULTS
  We did not find significant differences in survival between patients with FL who showed exclusively bcl-6 mutations and those without bcl-6 mutations, but those patients with a high International Progostic Index score and p53 mutations showed the lowest overall survival (p = 0.002).
  
  
  CONCLUSIONS
  These findings suggest that bcl-2/Jh lymphomas show molecular heterogeneity and that bcl-6 and p53 mutations may be acquired during the evolution of such lymphomas. Bcl-6 mutations, by themselves, do not seem to be associated with a bad prognosis. Rearrangements at the minor bcl-2 locus may have a different molecular evolution.
authors.affiliation: Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Bellido
authors.forename: Daniela
authors.initials: D
authors.lastname: Capello
authors.forename: Albert
authors.initials: A
authors.lastname: Altés
authors.forename: Camino
authors.initials: C
authors.lastname: Estivill
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Ramón
authors.initials: R
authors.lastname: Pujol
authors.forename: Ramón
authors.initials: R
authors.lastname: Bordes
authors.forename: Montserrat
authors.initials: M
authors.lastname: Baiget
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Jorge
authors.initials: J
authors.lastname: Sierra
authors.forename: Josep F
authors.initials: JF
authors.lastname: Nomdedéu
mesh_terms: D000328:Adult; D000368:Aged; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2 / Q000235:genetics*; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53