NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients

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NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients. / Willander, Kerstin; Dutta, Ravi Kumar; Ungerback, Jonas; Gunnarsson, Rebeqa; Juliusson, Gunnar; Fredrikson, Mats; Linderholm, Mats; Soderkvist, Peter.

In: BMC Cancer, Vol. 13, 274, 2013.

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Willander, K, Dutta, RK, Ungerback, J, Gunnarsson, R, Juliusson, G, Fredrikson, M, Linderholm, M & Soderkvist, P 2013, 'NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients', BMC Cancer, vol. 13, 274. https://doi.org/10.1186/1471-2407-13-274

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Willander, Kerstin ; Dutta, Ravi Kumar ; Ungerback, Jonas ; Gunnarsson, Rebeqa ; Juliusson, Gunnar ; Fredrikson, Mats ; Linderholm, Mats ; Soderkvist, Peter. / NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients. In: BMC Cancer. 2013 ; Vol. 13.

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TY - JOUR

T1 - NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients

AU - Willander, Kerstin

AU - Dutta, Ravi Kumar

AU - Ungerback, Jonas

AU - Gunnarsson, Rebeqa

AU - Juliusson, Gunnar

AU - Fredrikson, Mats

AU - Linderholm, Mats

AU - Soderkvist, Peter

N1 - The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hematology/Transplantation (013022014)

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Chronic lymphocytic leukemia

KW - NOTCH1 mutations

KW - TP53 mutations

KW - Prognostic markers

U2 - 10.1186/1471-2407-13-274

DO - 10.1186/1471-2407-13-274

M3 - Article

VL - 13

JO - BMC Cancer

JF - BMC Cancer

SN - 1471-2407

M1 - 274

ER -