title: B-cell receptor configuration and mutational analysis of patients with chronic lymphocytic leukaemia and trisomy 12 reveal recurrent molecular abnormalities.
abstract: Trisomy 12 (+12) is the third most frequent cytogenetic aberration in chronic lymphocytic leukaemia (CLL) retrievable both as the sole chromosomal abnormality or in association with additional alterations. NOTCH1 mutations are known to be more prevalent among +12 patients, whereas mutations of FBXW7, a gene involved in NOTCH1 degradation, that lead to the constitutional activation of NOTCH1 have not been investigated in this setting. We analyzed a unicentric cohort of 44 +12 patients with CLL for mutations of TP53, NOTCH1 and FBXW7 genes, and we correlated them with B-cell receptor (BCR) configurations. FBXW7, TP53 and NOTCH1 mutations were identified in 4.5%, 6.8% and 18.2% of patients, respectively. FBXW7 and NOTCH1 mutations appeared in a mutually exclusive fashion, suggesting that both aberrations might affect the same biological pathway. We found that 44.1% of +12 CLL patients had stereotyped B-cell receptors, which is significantly higher than that observed in patients with CLL and no +12 (27%, p = 0.01). Subsets #1, #8, #10, #28 and #59 were the most represented stereotyped patterns, and IGHV4-39*01 was the gene configuration most commonly used. There was a significantly higher risk for Richter's syndrome (RS) transformation in patients with NOTCH1 or FBXW7 mutations, with four of the seven (57%) patients developing RS and characterized at least by one of the two abnormalities. These observations suggest that, similarly to the aberrations of NOTCH1, FBXW7 gene mutations may also result in cell proliferation and evasion from apoptosis in patients with +12 CLL. Together with the extremely high frequency of stereotyped BCRs and RS transformation, these abnormalities appear to cluster in these CLL patients with additional chromosome 12, suggesting a connection with the prognosis of the disease.
authors.affiliation: Department of Hematology and Cell Therapy, S. Bortolo Hospital, Vicenza, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Falisi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Novella
authors.forename: Carlo
authors.initials: C
authors.lastname: Visco
authors.forename: Nicola
authors.initials: N
authors.lastname: Guercini
authors.forename: Francesco
authors.initials: F
authors.lastname: Maura
authors.forename: Ilaria
authors.initials: I
authors.lastname: Giaretta
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pomponi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Nichele
authors.forename: Silvia
authors.initials: S
authors.lastname: Finotto
authors.forename: Annamaria
authors.initials: A
authors.lastname: Montaldi
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.forename: Francesco
authors.initials: F
authors.lastname: Rodeghiero
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002881:Chromosomes, Human, Pair 12; D002999:Clone Cells / Q000473:pathology; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D016158:Genes, p53; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007399:Interphase / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013577:Syndrome; D014314:Trisomy; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases
keywords: FBXW7; NOTCH1; TP53; chronic lymphocytic leukaemia; stereotyped BCR