Home | About IJMPO | Editorial board | Search | Ahead of print | Current Issue | Archives | Instructions | Subscribe | Advertise | Contact us |  Login 
Indian Journal of Medical and Paediatric Oncology
Search Article 
  
Advanced search 
 

 Table of Contents      
ORIGINAL ARTICLE
Year : 2019  |  Volume : 40  |  Issue : 1  |  Page : 28-31  

The prevalence of BRAF V600E mutation in hairy cell leukemia: A systematic review and meta-analysis study


1 Department of Hematology and Medical Oncology, Kermanshah University of Medical Sciences, Kermanshah, Iran
2 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
3 Department of Nursing, Kermanshah University of Medical Sciences, Kermanshah, Iran
4 Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran

Date of Web Publication16-Apr-2019

Correspondence Address:
Edris Sadeghi
Department of Nursing, Kermanshah University of Medical Sciences, Kermanshah
Iran
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmpo.ijmpo_145_18

Rights and Permissions
  Abstract 

Background: BRAF V600E mutations were recently identified in the leukemic cells from patients with hairy cell leukemia (HCL) that this mutation in exon 15 is considered the disease-defining mutation in HCL. Objectives: This meta-analysis aimed to report the prevalence of BRAF V600E mutation in HCL patients. Methods: Three databases including PubMed, Scopus, and Web of Science up to 2017 were searched for the prevalence of BRAF mutation in HCL patients. A random effects meta-analysis was performed using the Comprehensive Meta-Analysis software version 2.0 with the event rate (ER) and 95% confidence interval (95% CI). Results: Out of 552 articles identified from the search, 11 were included included and were analyzed for meta-analysis study. The studies in meta-analysis included 437 patients with HCL, of which 353 (80.8%) patients had BRAF V600E mutation. The pooled ER of the studies was 81.5% (95% CI: 69.5%–89.5%). The Begg's test did not show publication bias, but the Egger's test showed publication bias. Conclusions: With regard to the mentioned limitations, the prevalence of BRAF mutation in HCL patients was >80%. In future studies, considering sex, age, and other variables can exactly show the correlation between these variables with the detection of BRAF mutation.

Keywords: BRAF, hairy cell leukemia, prevalence


How to cite this article:
Payandeh M, Sadeghi M, Sadeghi E, Iranshahi N. The prevalence of BRAF V600E mutation in hairy cell leukemia: A systematic review and meta-analysis study. Indian J Med Paediatr Oncol 2019;40:28-31

How to cite this URL:
Payandeh M, Sadeghi M, Sadeghi E, Iranshahi N. The prevalence of BRAF V600E mutation in hairy cell leukemia: A systematic review and meta-analysis study. Indian J Med Paediatr Oncol [serial online] 2019 [cited 2019 Jul 17];40:28-31. Available from: http://www.ijmpo.org/text.asp?2019/40/1/28/256155


  Introduction Top


Hairy cell leukemia (HCL) is a chronic B-cell lymphoid leukemia characterized by pancytopenia, splenomegaly, myelofibrosis, and the presence in peripheral blood, bone marrow, and spleen of atypical lymphoid cells with a hairy aspect.[1] There are approximately 1000 and 1600 new cases of HCL per year in the US and Europe, respectively. The prevalence of the disease is unknown, although HCL accounts for 2% of all types of leukemia, and the incidence of HCL increases annually.[2] Variant HCL (HCLv) is now included in the World Health Organization classification as a provisional entity and is no longer considered to be biologically related to classic HCL (HCLc). The clinical course of HCLv is variable, but usually more aggressive, and the median survival of patients with HCLv is significantly shorter than that of HCLc.[3] HCLc is a B-cell malignancy with distinctive immunophenotype, typically expressing CD20, CD22, CD25, CD11c, CD103, CD123, annexin A1, and tartrate-resistant acid phosphatase.[4] HCLc responds to purine nucleoside analogs, while HCLv cases are resistant and are more aggressive compared with the classic variant.[5] Clinically, HCL has an indolent course with splenomegaly, progressive cytopenias, low numbers of circulating leukemia cells, and no lymphadenopathy. BRAF V600E mutations were recently identified in the leukemic cells from patients with HCL.[6] This mutation in exon 15 is considered the disease-defining mutation in HCL, but single HCL cases lacking this mutation have been described.[7] It has demonstrated BRAF V600E-negative cases of HCL.[8] In some studies, BRAF V600E mutations were found in 100% cases of HCL.[9],[10] The aim of this meta-analysis study was to report the prevalence of BRAF V600E mutation in HCL patients.


  Methods Top


Search strategies and study criteria

The studies were searched in three databases (PubMed, Scopus, and Web of Science) up to December 2017 using the keywords of hairy cell leukemia or HCL and BRAF for the prevalence of BRAF mutation in HCL patients.

Study selection

One author (E.S) searched the articles and then the second author (M.S) was blinded to the first author. If there was any disagreement between the two authors, the problem was resolved with negotiation. All studies were searched for the evaluation of the prevalence of BRAF mutation in HCL patients. The inclusion criteria for the studies selected were as follows: (i) studies reporting the prevalence of BRAF and (ii) only studies with English language abstract. The exclusion criteria included the case reports, review articles, incomplete reports (no sufficient information), and letters.

Data extraction

The name of author, year of publication, publication country, total number of patients, and number of patients with BRAF mutation were the relevant data extracted from every study.

Statistical analysis

A random effects meta-analysis was performed by the Comprehensive Meta-Analysis software version 2.0 (CMA 2.0; Biostat Inc, Englewood, NJ). The event rate (ER) of the studies included was calculated for the estimation of the prevalence of BRAF mutation in HCL patients. Heterogeneity between estimates was evaluated by the Q and I2 statistics that, for the Q statistic, heterogeneity was considered if P < 0.1. Confidence interval (CI) was 95% and P (two-sided) <0.05 was considered to be statistically significant in this meta-analysis. The publication bias was assessed through funnel plot analysis with the Begg's and Egger's tests.


  Results Top


Out of 552 articles identified from the search, after excluding the studies, 25 studies were assessed for eligibility. Of these 25 studies, 14 studies were excluded based on reasons. Finally, 11 studies were included and were analyzed for meta-analysis study [Figure 1].
Figure 1: Flowchart of the study

Click here to view


The characteristics of the studies included in the meta-analysis are shown in [Table 1]. The studies included were between 2011 and 2016. Three studies were reported from Germany,[7],[11],[12] five studies from USA,[8],[10],[13],[14],[15] one study from Australia,[16] one study from Iraq,[17] and one study from Italy.[18] The studies in the meta-analysis included 437 patients with HCL, of which 353 (80.8%) patients had BRAF V600E mutation.
Table 1: The characteristics of the studies in meta-analysis (n=11)

Click here to view


The prevalence of BRAF mutation in HCL patients in the meta-analysis study is shown in [Figure 2]. The pooled ER of the studies was 81.5% (95% CI: 69.5%–89.5%) with I2 = 77.7%.
Figure 2: Forest plot of the prevalence of the studies included in the meta-analysis (n = 11)

Click here to view


Publication bias

Funnel plot of the studies for the prevalence of BRAF mutation in HCL patients is shown in [Figure 3]. The Begg's test did not show publication bias (P = 0.051), but Egger's test showed the publication bias (P = 0.010).
Figure 3: Funnel plot of the random effect of the studies for the prevalence of BRAF mutation in patients with hairy cell leukemia

Click here to view



  Discussion Top


This meta-analysis showed that the prevalence of BRAF V600E mutation in HCL patients was 81.5%. Boyd et al.[19] used high resolution melting analysis for detection of BRAF exon 15 mutations on formalin-fixed, paraffin-embedded (FFPE) tissues that this method may provide a useful tool for specialist hematopathology laboratories. Vemurafenib is used in treating patients with BRAF V600E mutation in HCL. BRAF mutation provides further opportunities for the use of a targeted therapy approach to improve outcome in HCL patients, especially for patients with relapsed or treatment-refractory disease.[20] The frequent nature of activating BRAF V600E mutations in HCL is fundamental in the pathogenetic understanding of this entity and will likely become an entity defining genetic aberration in future classifications.[11] Therefore, the detection of BRAF V600E mutations in HCL has important diagnostic utility.[13]

Two studies[19],[21] reported that the BRAF V600E mutation was present in all patients with HCL, and Xi et al.[8] reported in 79% of their HCLc cases using a pyrosequencing assay. Tiacci et al.[18] showed that BRAF V600E mutation can serve as a new diagnostic tool to distinguish HCL from other morphologically similar B-cell neoplasms.

There are several methods used in the studies including Sanger sequencing, high-resolution melting, allele-specific polymerase chain reaction, and pyrosequencing that most of them used either fresh or frozen tissue or stringent criteria for accepting FFPE specimens.[14] As these studies investigated only exon 15 of the BRAF gene, one study extended our sequencing approach to exon 11, which harbors a second hotspot of BRAF mutations in solid tumors.[7] In the routine diagnostic setting, It is suggested the screening of BRAF V600E-negative HCL for alternative exon 11 mutations.[7]

One study[6] reported that the BRAF V600E mutation was detected in 100% of HCLc versus none of the HCLv patients. Another study[8] showed that BRAF was mutated in 79% of HCLc and none of the HCLv patients. Therefore, used methods, different subtypes of HCL, and exons checked can change the percentage of BRAF mutation and cause the difference between the results in the studies.

Limitations

  1. Difference in the detection methods of BRAF mutation in HCL patients
  2. Low number of patients in more studies
  3. Unknown age and gender in a number of studies
  4. Difference in the number of patients in subgroups of HCL among the studies (HCLc and HCLv).



  Conclusions Top


With regard to the mentioned limitations, the prevalence of BRAF mutation in HCL patients was >80%. In the future studies, sex, age, and other variables can exactly show the correlation between these variables with the detection of BRAF mutation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Payandeh M, Sadeghi M, Sadeghi E. Hairy cell leukemia: A retrospective study on 11 patients in the Western of Iran. Int J Hematol Oncol Stem Cell Res 2015;9:133-7.  Back to cited text no. 1
    
2.
Shackelford RE, Heldmann M, Eskandari F, Joshi N, Browning J, Maxwell N, et al. Marked retroperitoneal lymphadenopathy in hairy cell leukemia: A case report. Case Rep Oncol 2013;6:493-6.  Back to cited text no. 2
    
3.
Robak T. Management of hairy cell leukemia variant. Leuk Lymphoma 2011;52 Suppl 2:53-6.  Back to cited text no. 3
    
4.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein, H, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed., Vol. 2. Lyon, France: World Health Organization; 2008.  Back to cited text no. 4
    
5.
Hsieh YC, Chang ST, Chuang SS, Lu CL, Tsao CJ, Lin CN, et al. Hairy cell leukemia and variant in Taiwan: Report of a variant case and literature review. Int J Clin Exp Pathol 2011;4:183-9.  Back to cited text no. 5
    
6.
Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med 2011;364:2305-15.  Back to cited text no. 6
    
7.
Tschernitz S, Flossbach L, Bonengel M, Roth S, Rosenwald A, Geissinger E, et al. Alternative BRAF mutations in BRAF V600E-negative hairy cell leukaemias. Br J Haematol 2014;165:529-33.  Back to cited text no. 7
    
8.
Xi L, Arons E, Navarro W, Calvo KR, Stetler-Stevenson M, Raffeld M, et al. Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. Blood 2012;119:3330-2.  Back to cited text no. 8
    
9.
Tiacci E, Schiavoni G, Forconi F, Santi A, Trentin L, Ambrosetti A, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood 2012;119:192-5.  Back to cited text no. 9
    
10.
Blombery PA, Wong SQ, Hewitt CA, Dobrovic A, Maxwell EL, Juneja S, et al. Detection of BRAF mutations in patients with hairy cell leukemia and related lymphoproliferative disorders. Haematologica 2012;97:780-3.  Back to cited text no. 10
    
11.
Andrulis M, Penzel R, Weichert W, von Deimling A, Capper D. Application of a BRAF V600E mutation-specific antibody for the diagnosis of hairy cell leukemia. Am J Surg Pathol 2012;36:1796-800.  Back to cited text no. 11
    
12.
Schnittger S, Bacher U, Haferlach T, Wendland N, Ulke M, Dicker F, et al. Development and validation of a real-time quantification assay to detect and monitor BRAFV600E mutations in hairy cell leukemia. Blood 2012;119:3151-4.  Back to cited text no. 12
    
13.
Brown NA, Betz BL, Weigelin HC, Elenitoba-Johnson KS, Lim MS, Bailey NG, et al. Evaluation of allele-specific PCR and immunohistochemistry for the detection of BRAF V600E mutations in hairy cell leukemia. Am J Clin Pathol 2015a;143:89-99.  Back to cited text no. 13
    
14.
Brown NA, Weigelin HC, Bailey N, Laliberte J, Elenitoba-Johnson KS, Lim MS, et al. Requisite analytic and diagnostic performance characteristics for the clinical detection of BRAF V600E in hairy cell leukemia: A comparison of 2 allele-specific PCR assays. Appl Immunohistochem Mol Morphol 2015b;23:590-600.  Back to cited text no. 14
    
15.
Verma S, Greaves WO, Ravandi F, Reddy N, Bueso-Ramos CE, O'Brien S, et al. Rapid detection and quantitation of BRAF mutations in hairy cell leukemia using a sensitive pyrosequencing assay. Am J Clin Pathol 2012;138:153-6.  Back to cited text no. 15
    
16.
Thomas C, Amanuel B, Finlayson J, Grieu-Iacopetta F, Spagnolo DV, Erber WN, et al. BRAF mutation detection in hairy cell leukaemia from archival haematolymphoid specimens. Pathology 2015;47:349-54.  Back to cited text no. 16
    
17.
Zahraa M. Al Taee. Investigation of three BRAF V600E mutations related to hairy cell leukemia in Al-Hillah city. Res J Pharm Biol Chem Sci 2016;7:1658.  Back to cited text no. 17
    
18.
Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med 2011b;364:2305-15.  Back to cited text no. 18
    
19.
Boyd EM, Bench AJ, van 't Veer MB, Wright P, Bloxham DM, Follows GA, et al. High resolution melting analysis for detection of BRAF exon 15 mutations in hairy cell leukaemia and other lymphoid malignancies. Br J Haematol 2011;155:609-12.  Back to cited text no. 19
    
20.
Roberts PJ, Der CJ. Targeting the raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 2007;26:3291-310.  Back to cited text no. 20
    
21.
Tiacci E, Schiavoni G, Forconi F, Santi A, Trentin L, Ambrosetti A, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood 2012a;119:192-5.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
   Abstract
  Introduction
  Methods
  Results
  Discussion
  Conclusions
   References
   Article Figures
   Article Tables

 Article Access Statistics
    Viewed184    
    Printed13    
    Emailed0    
    PDF Downloaded44    
    Comments [Add]    

Recommend this journal