Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients

Authors: Kerstin Willander, Ravi Kumar Dutta, Jonas Ungerbäck, Rebeqa Gunnarsson, Gunnar Juliusson, Mats Fredrikson, Mats Linderholm, Peter Söderkvist

Published in: BMC Cancer | Issue 1/2013

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Chiorazzi N, Rai KR, Ferranini M: Chronic lymphocytic leukemia. N Engl J Med. 2005, 352: 805-815.CrossRef
2.
Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, Werner L, Sivachenko A, DeLuca DS, Zhang L, Zhang W, Zhang W, Vartanov AR, Fernandes SM, Goldstein NR, Folco EG, Cibulskis K, Tesar B, Sievers QL, Shefler E, Gabriel S, Hacohen N, Reed R, Meyerson M, Golub TR, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ: SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011, 365: 2497-2506.CrossRefPubMedPubMedCentral
3.
Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N: IgV gene mutation status and CD 38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999, 94: 1840-1847.PubMed
4.
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK: Unmutated IgV(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999, 94: 1848-1854.PubMed
5.
Döhner H, Stielgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000, 343: 1910-1916.CrossRefPubMed
6.
Sportoletti P, Baldoni S, Cavalli L, Del Papa B, Bonifacio E, Ciurnelli R, Bell AS, Di Tommaso A, Rosati E, Crescenzi B, Mecucci C, Screpanti I, Marconi P, Martelli MF, Di Ianni M, Falzetti F: Notch1 PEST domain mutation is an adverse prognostic factor in B-CLL. British Journal of Haematology. 2010, 151: 404-406.CrossRefPubMed
7.
Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N, Escaramis G, Jares P, Beà S, González-Díaz M, Bassaganyas L, Baumann T, Juan M, López-Guerra M, Colomer D, Tubío JM, López C, Navarro A, Tornador C, Aymerich M, Rozman M, Hernández JM, Puente DA, Freije JM, Velasco G, Gutiérrez-Fernández A, Costa D, Carrió A, Guijarro S, Enjuanes A: Whole genome sequencing identifies recurrent mutations in chronic lymphocytic leukemia. Nature. 2011, 475: 101-105.CrossRefPubMedPubMedCentral
8.
Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J, Grunn A, Fangazio M, Capello D, Monti S, Cresta S, Gargiulo E, Forconi F, Guarini A, Arcaini L, Paulli M, Laurenti L, Larocca LM, Marasca R, Gattei V, Oscier D, Bertoni F, Mullighan CG, Foá R, Pasqualucci L, Rabadan R, Dalla-Favera R, Gaidano G: Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011, 208: 1389-1401.CrossRefPubMedPubMedCentral
9.
Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F, Marasca R, Laurenti L, Bruscaggin A, Cerri M, Monti S, Cresta S, Famà R, De Paoli L, Bulian P, Gattei V, Guarini A, Deaglio S, Capello D, Rabadan R, Pasqualucci L, Dalla-Favera R, Foà R, Gaidano G: Mutations of Notch1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012, 119: 521-529.CrossRefPubMedPubMedCentral
10.
Shedden K, Li Y, Quillette P, Malek SN: Characteristics of chronic lymphocytic leukemia with somatically acquired mutations in exon 34. Leukemia. 2011, 26: 1108-1110.CrossRefPubMedPubMedCentral
11.
Mansouri L, Cahill N, Gunnarsson R, Smedby KE, Tjönnfjord E, Hjalgrim H, Juliusson G, Geisler C, Rosenquist R: NOTCH1 and SF3B1 mutations can be added to the hierarchical prognostic classification in chronic lymphocytic leukemia. Leukemia. 2013, 27: 512-514.CrossRefPubMed
12.
Rosati E, Sabatini R, Rampino G, Tabilio A, Di Ianni M, Fettucciari K, Bartoli A, Coaccioli S, Screpanti I, Marconi P: Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood. 2009, 113: 856-865.CrossRefPubMed
13.
Radtke F, Wilson A, Mancini SJC, Robson MacDonald H: Notch regulation of lymphocyte development and function. Nature Immunology. 2004, 5: 247-253.CrossRefPubMed
14.
Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A, Barnes KC, O’Neil J, Neuberg D, Weng AP, Aster JC, Sigaux F, Soulier J, Look AT, Young RA, Califano A, Ferrando AA: Notch1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. PNAS. 2006, 103: 18261-18266.CrossRefPubMedPubMedCentral
15.
Lee SY, Kumano K, Nakazaki K, Sanada M, Matsumoto A, Yamamoto G, Nannya Y, Suzuki R, Ota S, Ota Y, Izutsu K, Sakata-Yanagimoto M, Hangaishi A, Yagita H, Fukayama M, Seto M, Kurokawa M, Ogawa S, Chiba S: Gain-of-function mutations and copy number increases of Notch2 diffuse large B-cell lymphoma. Cancer Science. 2009, 100: 920-926.CrossRefPubMed
16.
Hubmann R, Schwarzmeier JD, Sheta M, Hilgarth M, Duechler M, Dettke M, Berger R: Notch2 is involved in overexperssion of CD23 in B-cell chronic lymphocytic leukemia. Blood. 2002, 99: 3742-3747.CrossRefPubMed
17.
Willander K, Ungerbäck J, Karlsson K, Fredrikson M, Söderkvist P, Linderholm M: MDM2 SNP309 promoter polymorphism, an independent prognostic factor in chronic lymphocytic leukemia. European Journal of Haematology. 2010, 85: 251-256.CrossRefPubMed
18.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ: Guidelines for diagnosis and treatment of chronic lymphocytic leukemia: a report from an international workshop on chronic lymphocytic leukemia updating the national cancer institute working group 1996 guidelines. Blood. 2008, 111: 5446-5456.CrossRefPubMedPubMedCentral
19.
Orita M, Suzuki Y, Sekiya T, Hayashi K: Rapid and sensitive detection of point mutations and DNA polymorphism using the polymerase chain reaction. Genomics. 1989, 5: 874-879.CrossRefPubMed
20.
van Dongen JJ, Langerak AW, Brüggemann M, Evans PA, Hummel M, Lavender FL, Delabesse E, Davi F, Schuuring E, García-Sanz R, van Krieken JH, Droese J, González D, Bastard C, White HE, Spaargaren M, González M, Parreira A, Smith JL, Morgan GJ, Kneba M, Macintyre EA: Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003, 17: 2257-2317.CrossRefPubMed
21.
Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004, 306: 269-271.CrossRefPubMed
22.
Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A, Shefler E, Ramos AH, Stojanov P, Carter SL, Voet D, Cortés ML, Auclair D, Berger MF, Saksena G, Guiducci C, Onofrio RC, Parkin M, Romkes M, Weissfeld JL, Seethala RR, Wang L, Rangel-Escareño C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J: The mutational landscape of head and neck squamous cell carcinoma. Science. 2011, 333: 1157-1160.CrossRefPubMedPubMedCentral
23.
Rossi D, Trifonov V, Fangazio M, Bruscaggin A, Rasi S, Spina V, Monti S, Vaisitti T, Arruga F, Famà R, Ciardullo C, Greco M, Cresta S, Piranda D, Holmes A, Fabbri G, Messina M, Rinaldi A, Wang J, Agostinelli C, Piccaluga PP, Lucioni M, Tabbò F, Serra R, Franceschetti S, Deambrogi C, Daniele G, Gattei V, Marasca R: The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med. 2012, 209: 1537-1551.CrossRefPubMedPubMedCentral
24.
Kiel MJ, Velusamy T, Betz BL, Zhao L, Weigelin HG, Chiang MY, Huebner-Chan DR, Bailey NG, Yang DT, Bhagat G, Miranda RN, Bahler DW, Medeiros LJ, Lim MS, Elenitoba-Johnson KS: Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. J Exp Med. 2012, 209: 1553-1565.CrossRefPubMedPubMedCentral
25.
Zenz T, Kröber A, Scherer K, Häbe S, Bühler A, Benner A, Denzel T, Winkler D, Edelmann J, Schwänen C, Döhner H, Stilgenbauer S: Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood. 2008, 112: 3322-3329.CrossRefPubMed
26.
Baletti V, Bottoni A, Palamarchuk A, Alder H, Rassenti LZ, Kipps TJ: Notch1 mutations in CLL associated with trisomy 12. Blood. 2012, 119: 329-331.CrossRef
27.
Del Guidice I, Rossi D, Chiaretti S, Marinelli M, Tavolaro S, Gabrielli S, Laurenti L, Marasca R, Rasi S, Fangazio M, Guarini A, Gaidano G, Foà R: Notch1 mutations in +12 chronic lymphocytic leukemia (CLL) confer and unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL. Haematologica. 2012, 97: 437-441.CrossRef
28.
Secchiero P, Melloni E, di Iasio MG, Tiribelli M, Rimondi E, Corallini F, Gattei V, Zauli G: Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of negative feedback antiapoptotic mechanism. Blood. 2009, 113: 4300-4308.CrossRefPubMed
29.
Paolo Dotto G: Crosstalk of Notch with p53 and p63 in cancer growth control. Nature Rev. Cancer. 2009, 9: 587-595.CrossRef
30.
Rossi D, Rasi S, Spina V, Fangazio M, Monti S, Greco M, Ciardullo C, Famà R, Cresta S, Bruscaggin A, Laurenti L, Martini M, Musto P, Forconi F, Marasca R, Larocca LM, Foà R, Gaidano G: Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome. British Journal of Haematoloy. 2012, 158: 426-229.CrossRef
31.
Pospisilova S, Gonzalez D, Malcikova J, Trbusek M, Rossi D, Kater AP, Cymbalista F, Eichhorst B, Hallek M, Döhner H, Hillmen P, van Oers M, Gribben J, Ghia P, Montserrat E, Stilgenbauer S, Zenz T: ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia. 2012, 26: 1458-1461.CrossRefPubMed
32.
Zenz T, Gribben JG, Hallek M, Döhner H, Keating MJ, Stielgenbauer S: Risk categories and refractory CLL in era of chemoimmunotherapy. Blood. 2012, 119: 4101-4107.CrossRefPubMed
Metadata
Title
NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients
Authors
Kerstin Willander
Ravi Kumar Dutta
Jonas Ungerbäck
Rebeqa Gunnarsson
Gunnar Juliusson
Mats Fredrikson
Mats Linderholm
Peter Söderkvist
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-274

Other articles of this Issue 1/2013

BMC Cancer 1/2013 Go to the issue

Research article

Preoperative core needle biopsy is accurate in determining molecular subtypes in invasive breast cancer

Research article

Genetic association between selected cytokine genes and glioblastoma in the Han Chinese population

Research article

Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death

Research article

IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma

Research article

Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness–a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer

Research article

Wnt signaling in triple negative breast cancer is associated with metastasis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits