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NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients

Willander, Kerstin ; Dutta, Ravi Kumar ; Ungerback, Jonas ; Gunnarsson, Rebeqa LU ; Juliusson, Gunnar LU ; Fredrikson, Mats ; Linderholm, Mats and Soderkvist, Peter (2013) In BMC Cancer 13.
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Chronic lymphocytic leukemia, NOTCH1 mutations, TP53 mutations, Prognostic markers
in
BMC Cancer
volume
13
article number
274
publisher
BioMed Central
external identifiers
  • wos:000319998800001
  • scopus:84878390720
  • pmid:23734977
ISSN
1471-2407
DOI
10.1186/1471-2407-13-274
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hematology/Transplantation (013022014)
id
3f3304bc-46dc-4f0c-b8a6-b53bd9bb593e (old id 3921145)
date added to LUP
2016-04-01 14:09:38
date last changed
2020-01-12 15:05:19
@article{3f3304bc-46dc-4f0c-b8a6-b53bd9bb593e,
  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.},
  author       = {Willander, Kerstin and Dutta, Ravi Kumar and Ungerback, Jonas and Gunnarsson, Rebeqa and Juliusson, Gunnar and Fredrikson, Mats and Linderholm, Mats and Soderkvist, Peter},
  issn         = {1471-2407},
  language     = {eng},
  publisher    = {BioMed Central},
  series       = {BMC Cancer},
  title        = {NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients},
  url          = {https://lup.lub.lu.se/search/ws/files/3820201/4145691},
  doi          = {10.1186/1471-2407-13-274},
  volume       = {13},
  year         = {2013},
}