title: NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients.
abstract: BACKGROUND
  NOTCH1 PEST domain mutations in chronic lymphocytic leukemia have recently been shown to be of prognostic relevance. Both NOTCH1 and NOTCH2 are constitutively activated in B-cell CLL but not expressed in normal B cells and may be involved in survival and resistance to apoptosis in CLL. We screened for mutations in different parts of both NOTCH1 and NOTCH2 genes and related the changes to survival and other known risk factors.
  
  
  METHODS
  In a cohort of 209 CLL patients, we used single strand conformation analysis to determine which of the samples carrying the NOTCH mutations and direct dideoxy sequencing was used to determine the exact nucleotide changes. Kaplan-Meier curves and log rank test were used to determine overall survival for NOTCH1 mutated cases and Cox regression analysis was used to calculate hazardous ratios.
  
  
  RESULTS
  In the present study, we found NOTCH1 PEST domain mutations in 6.7% of the cases. A shorter overall survival was found in patients with NOTCH1 mutations compared to wildtype (p = 0.049). Further, we also examined the extracellular and the heterodimerisation domains of the NOTCH1 gene and the PEST domain and heterodimerisation domain of the NOTCH2 gene, but no mutations were found in these regions. NOTCH1 mutations were most commonly observed in patients with unmutated IGHV gene (10/14), and associated with a more aggressive disease course. In addition, NOTCH1 mutations were almost mutually exclusive with TP53 mutations. In the combined group of NOTCH1 (6.7%) or TP53 (6.2%) mutations, a significant difference in overall survival compared to the wildtype NOTCH1 and TP53 was found (p = 0.002).
  
  
  CONCLUSIONS
  Both NOTCH1 and TP53 mutations seem to be independent predictive markers for worse outcome in CLL-patients and this study emphasizes the contention that NOTCH1 mutations is a novel risk marker.
authors.affiliation: Department of Clinical and Experimental Medicine, Department of Hematology, County Council of Östergötland, Linköping University, SE-58185 Linköping, Sweden. kerstin.willander@liu.se
authors.forename: Kerstin
authors.initials: K
authors.lastname: Willander
authors.forename: Ravi Kumar
authors.initials: RK
authors.lastname: Dutta
authors.forename: Jonas
authors.initials: J
authors.lastname: Ungerbäck
authors.forename: Rebeqa
authors.initials: R
authors.lastname: Gunnarsson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Juliusson
authors.forename: Mats
authors.initials: M
authors.lastname: Fredrikson
authors.forename: Mats
authors.initials: M
authors.lastname: Linderholm
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D016016:Proportional Hazards Models; D051881:Receptor, Notch1 / Q000235:genetics*
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1