title: Patients with chronic lymphocytic leukemia with mutated VH genes presenting with Binet stage B or C form a subgroup with a poor outcome.
abstract: OBJECTIVE
  The immunoglobulin VH gene mutation status is a strong prognostic indicator in B-cell chronic lymphocytic leukemia (CLL), since unmutated VH genes are correlated with short survival. However, the traditional cut-off level dividing mutated and unmutated cases, i.e. more or less than 2% mutations, has been questioned and other cut-offs have been suggested. We investigated whether an alternative cut-off should be applied and the relation of mutational status to another prognostic marker, Binet staging.
  
  
  METHODS
  VH gene mutation status was assessed in 332 CLL cases by polymerase chain reaction amplification and nucleotide sequencing and was further correlated with overall survival using different VH mutation cut-offs (1-7%) and Binet stage.
  
  
  RESULTS
  After testing different mutation borders, the 2% cut-off remained the best discriminative level for determining prognosis. Interestingly, prognostic stratification was improved by combining the information on VH gene mutation status with that of Binet stage: unmutated cases (all stages, n=151, mutated cases with stage A (n=77), and mutated cases with stage B or C (n=37) had a median survival of 82, 179 and 74 months, respectively.
  
  
  CONCLUSIONS
  CLL cases displaying mutated VH genes with Binet stage B or C had a survival similar to that of unmutated cases and significantly shorter than that of mutated stage A CLL. Our result reveals clinical heterogeneity within the VH mutated CLL group by inclusion of Binet stage data, a finding which is of importance when considering surrogate marker(s) for VH mutation status.
authors.affiliation: Dept. of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Gerard
authors.initials: G
authors.lastname: Tobin
authors.forename: Ulf
authors.initials: U
authors.lastname: Thunberg
authors.forename: Anna
authors.initials: A
authors.lastname: Laurell
authors.forename: Karin
authors.initials: K
authors.lastname: Karlsson
authors.forename: Anna
authors.initials: A
authors.lastname: Aleskog
authors.forename: Kerstin
authors.initials: K
authors.lastname: Willander
authors.forename: Ola
authors.initials: O
authors.lastname: Söderberg
authors.forename: Mats
authors.initials: M
authors.lastname: Merup
authors.forename: Juhani
authors.initials: J
authors.lastname: Vilpo
authors.forename: Magnus
authors.initials: M
authors.lastname: Hultdin
authors.forename: Christer
authors.initials: C
authors.lastname: Sundström
authors.forename: Göran
authors.initials: G
authors.lastname: Roos
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D000328:Adult; D018572:Disease-Free Survival; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin / Q000502:physiology*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D009367:Neoplasm Staging; D027041:Somatic Hypermutation, Immunoglobulin; D016896:Treatment Outcome
chemical_list: D007135:Immunoglobulin Variable Region