Skip to main content

Advertisement

SpringerLink
Log in

High-resolution Melting Analysis for NOTCH1 c.7541-7542delCT Mutation in Chronic Lymphocytic Leukemia: Prognostic Significance in Egyptian Patients

  • Original Article
  • Published:
Indian Journal of Hematology and Blood Transfusion Aims and scope Submit manuscript

Abstract

The present study aimed to detect the prevalence of NOTCH1 c.7541-7542delCT mutation in Egyptian CLL patients using HRM assay and to assess its relation to patients’ survival. The study included 50 newly diagnosed treatment-naïve CLL patients and 50 age and sex matched healthy controls. NOTCH1 c.7541-7542delCT mutation was detected using High-resolution melting (HRM) assay and direct Sanger sequencing. Outcome parameters included progression free survival (PFS) and overall survival (OS). NOTCH1 c.7541-7542delCT mutation was detected in 5 (10.0%) of CLL patients. No controls had NOTCH1 c.7541-7542delCT mutation. Similar results were obtained by direct Sanger sequencing yielding a sensitivity and specificity of 100.0% for HRM in detection of NOTCH1 c.7541-7542delCT mutation in the studied patients. In univariate analysis, predictors of OS included Trisomy 12, high LDH, presence of NOTCH1 c.7541-7542delCT mutation and lack of CR. In multivariate analysis, only lack of CR was found as a significant predictor of OS. HRM analysis is a sensitive method for detection of NOTCH1 c.7541-7542delCT mutation in CLL patients. This mutation may be linked to poor disease prognosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Guièze R, Wu CJ (2015) Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. Blood 126(4):445–453 (PMID: 26065654)

    Article  CAS  Google Scholar 

  2. Amaya-Chanaga CI, Rassenti LZ (2016) Biomarkers in chronic lymphocytic leukemia: clinical applications and prognostic markers. Best Pract Res Clin Haematol 29(1):79–89 (PMID: 27742074)

    Article  Google Scholar 

  3. Gharaibeh L, Elmadany N, Alwosaibai K et al (2020) Notch1 in cancer therapy: possible clinical implications and challenges. Mol Pharmacol 98(5):559–576 (PMID: 32913140)

    Article  CAS  Google Scholar 

  4. Rosati E, Baldoni S, De Falco F, Del Papa B, Dorillo E, Rompietti C, Albi E, Falzetti F, Di Ianni M, Sportoletti P (2018) NOTCH1 aberrations in chronic lymphocytic leukemia. Front Oncol 27(8):229. https://doi.org/10.3389/fonc.2018.00229.PMID:29998084;PMCID:PMC6030253

    Article  Google Scholar 

  5. Xu JJ, Yao FR, Jiang M et al (2017) High-resolution melting analysis for rapid and sensitive NOTCH1 screening in chronic lymphocytic leukemia. Int J Mol Med 39(2):415–422 (PMID: 28075457)

    Article  CAS  Google Scholar 

  6. Vavrova E, Kantorova B, Vonkova B et al (2017) Fragment analysis represents a suitable approach for the detection of hotspot c.7541_7542delCT NOTCH1 mutation in chronic lymphocytic leukemia. Leuk Res. 60:145–150 (PMID: 28837890)

    Article  CAS  Google Scholar 

  7. Swerdlow SH, Campo E, Pileri SA et al (2016) The 2016 revision of the world health organization classification of lymphoid neoplasms. Blood 127(20):2375–2390

    Article  CAS  Google Scholar 

  8. Ihle MA, Fassunke J, König K et al (2014) Comparison of high resolution melting analysis, pyrosequencing, next generation sequencing and immunohistochemistry to conventional Sanger sequencing for the detection of p.V600E and non-p.V600E BRAF mutations. BMC Cancer 10(14):13 (PMID: 24410877)

    Article  Google Scholar 

  9. Zhang H, Zhang X, Wang J et al (2015) Comparison of high-resolution melting analysis, sanger sequencing and ARMS for KRAS mutation detection in metastatic colorectal cancer. Clin Lab 61(3–4):435–439 (PMID: 25975014)

    PubMed  CAS  Google Scholar 

  10. Vossen RH, Aten E, Roos A et al (2009) High-resolution melting analysis (HRMA): more than just sequence variant screening. Hum Mutat 30(6):860–866 (PMID: 19418555)

    Article  CAS  Google Scholar 

  11. Pozzo F, Bittolo T, Arruga F et al (2016) NOTCH1 mutations associate with low CD20 level in chronic lymphocytic leukemia: evidence for a NOTCH1 mutation-driven epigenetic dysregulation. Leukemia 30(1):182–189 (PMID: 26165233)

    Article  CAS  Google Scholar 

  12. Arruga F, Gizdic B, Bologna C et al (2017) Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22. Leukemia 31(9):1882–1893 (PMID: 28017968)

    Article  CAS  Google Scholar 

  13. Srinivasan VK, Naseem S, Varma N et al (2020) Genomic alterations in chronic lymphocytic leukemia and their correlation with clinico-hematological parameters and disease progression. Blood Res 55(3):131–138

    Article  CAS  Google Scholar 

  14. Rossi D, Rasi S, Fabbri G et al (2012) Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood 119(2):521–529 (PMID: 22077063)

    Article  CAS  Google Scholar 

  15. Del Poeta G, Biagi A, Laurenti L et al. (2020) Impaired nodal shrinkage and apoptosis define the independent adverse outcome of NOTCH1 mutated patients under ibrutinib therapy in chronic lymphocytic leukaemia. Haematologica. (PMID: 32732360)

  16. Messina M, Del Giudice I, Khiabanian H et al (2014) Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness. Blood 123(15):2378–2388 (PMID: 24550227)

    Article  CAS  Google Scholar 

  17. Gallo Llorente L, Luther H, Schneppenheim R et al (2014) Identification of novel NOTCH1 mutations: increasing our knowledge of the NOTCH signaling pathway. Pediatr Blood Cancer 61(5):788–796 (PMID: 24249312)

    Article  CAS  Google Scholar 

  18. Benedetti D, Tissino E, Pozzo F et al (2018) NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways. Leukemia 32(3):654–662 (PMID: 28935990)

    Article  CAS  Google Scholar 

  19. López-Guerra M, Xargay-Torrent S, Rosich L et al (2015) The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells. Leukemia 29(1):96–106 (PMID: 24781018)

    Article  CAS  Google Scholar 

  20. Silkenstedt E, Arenas F, Colom-Sanmartí B et al (2019) Notch1 signaling in NOTCH1-mutated mantle cell lymphoma depends on Delta-Like ligand 4 and is a potential target for specific antibody therapy. J Exp Clin Cancer Res. 38(1):446 (PMID: 31676012)

    Article  CAS  Google Scholar 

  21. López-Guerra M, Xargay-Torrent S, Fuentes P et al (2020) Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells. Oncogene 39(6):1185–1197 (PMID: 31616059)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

None.

Funding

The research is self-funded from the authors.

Author information

Authors and Affiliations

  1. Clinical Pathology Department, Faculty of Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt

    Dalia Sherief, Asmaa Hassan, Eman Habeeb & Nahla Nosair

  2. Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    Maaly Mabrouk, Sarah Shoeib & Mona Watany

  3. Department of Pediatrics, Faculty of Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt

    Heba Reyad

  4. Internal Medicine Department, Faculty of Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt

    Tamer Haydra

Authors
  1. Dalia Sherief
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Asmaa Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eman Habeeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nahla Nosair
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maaly Mabrouk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sarah Shoeib
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heba Reyad
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tamer Haydra
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mona Watany
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dalia Sherief.

Ethics declarations

Competing interests

Authors state no conflict of interest.

Ethical Approval

The local Institutional Review Board deemed the study exempt from review.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sherief, D., Hassan, A., Habeeb, E. et al. High-resolution Melting Analysis for NOTCH1 c.7541-7542delCT Mutation in Chronic Lymphocytic Leukemia: Prognostic Significance in Egyptian Patients. Indian J Hematol Blood Transfus 38, 675–679 (2022). https://doi.org/10.1007/s12288-022-01535-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12288-022-01535-z

Keywords

Search

Navigation