Highlights
- •BCL2 gene rearrangement is considered a hallmark of folicular lymphoma.
- •The real frequency of BCL2 rearrangement in follicular lymphoma has not been systematically explored.
- •The frequency of BCL2 rearrangement is lower than expected in our series of follicular lymphomas.
- •BCL2 rearrangement should be assessed at diagnosis, if it supposed to be used as a marker in the follow up.
- •Genetic alterations may drive lympohomagenesis in BCL2-negative follicular lymphoma.
Abstract
BCL2 rearrangement is reported to be an early pathogenetic event in follicular lymphoma
(FL) and it is considered as a reliable marker in the follow up of the disease. We
aimed to investigate the frequency of BCL2 rearrangement in FLs from northwestern Italy, to evaluate their clinicopathological
features, and to investigate alternative genetic aberrations in BCL2-negative FLs.
We collected a series of 76 consecutive FLs diagnosed between 2013 and 2016. All lymphomas
underwent histopathological review. Interphasic fluorescent in situ hybridization (FISH) was performed with break apart probes targeting BCL2, IGH, BCL6 and MYC on paraffin embedded (PE) and fresh frozen (FF) specimens. 1p36 region and p53 locus in BLC2-negative cases were investigated using dual color probes. Karyotype analysis was
available in a subset of cases.
BCL2 rearrangements were detected in 39 cases (51,3%). Of the remaining 37, 6 showed IGH rearrangement, and were further tested: 1 showed variant BCL2 translocation, 1 had BCL6 rearrangement, and the other 4 were negative for further gene rearrangements. FISH on FF specimens detected small BCL2+ clones in cases otherwise categorized as BCL2-. 1p36 and p53 deletion were observed in 1 and 8 BCL2- FLs, respectively. Karyotype analysis documented 3q, 1p and BCL6 alternative abnormalities in 3 cases.
In conclusion, BCL2 rearrangement is not a constant finding in FL, its frequency being probably affected
by geographical factors. Thus, it should not be considered as a reliable molecular
marker in the follow up of the disease, unless it is found to be present at the initial
diagnosis of FL. Alternative genetic aberrations exist in BCL2-negative cases.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Cancer GeneticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- WHO classification of tumours of haematopoietic and lymphoid tissues.Revised 4th edition. IARC, Lyon2017
- Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma.Blood. 2013; 121: 1604-1611
- The 14;18 translocation in European cases of follicular lymphoma: comparison of Southern blotting and the polymerase chain reaction.Br J Haematol. 1990; 76: 58-64
- Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation.Blood. 2002; 99: 4265-4275
- Frequencies of BCL2 and BCL6 translocations in representative Chinese follicular lymphoma patients: morphologic, immunohistochemical, and FISH analyses.Diagn Mol Pathol. 2012; 21: 234-240
- Geographic variance in the frequency of the t(14;18) translocation in follicular lymphoma: an Israeli series compared to the world.Blood Cells Mol Dis. 1998; 24: 62-72
- The incidence of non-Hodgkin's lymphoma and its histologic subtypes in Asian migrants to the United States and their descendants.Cancer Causes Control. 1996; 7: 224-230
- Unraveling tumor heterogeneity in an apparently monolithic disease: BCL2 and other players in the genetic landscape of nodal follicular lymphoma.Front Med (Lausanne). 2019; 6: 44
- Specificity of interphase fluorescent in situ hybridization for detection of chromosome aberrations in tumor pathology.Cancer Genet Cytogenet. 2004; 155: 143-148
- BCL2, BCL6, MYC, MALT 1, and BCL10 rearrangements in nodal diffuse large B-cell lymphomas: a multicenter evaluation of a new set of fluorescent in situ hybridization probes and correlation with clinical outcome.Hum Pathol. 2009; 40: 645-652
- Early involvement of 6q in surface epithelial ovarian tumors.Cancer Res. 1996; 56: 4493-4498
- McGowan-Jordan J. Simons A. Schmid M. ISCN 2016: An International System for Human Cytogenomic Nomenclature. Cytogen Gen Res. 2016 (149(1-2))
- Composite follicular lymphoma and “early” (in situ and mantle zone growth pattern) mantle cell neoplasia: a rare entity with peculiar cytogenetic and clinical features.Pathol Res Pract. 2020; 216153067
- High frequency of t(14;18)translocation breakpoints outside of major breakpoint and minor cluster regions in follicular lymphomas: improved polymerase chain reaction protocols for their detection.Am J Pathol. 2002; 160: 823-832
- Detection of BCL2 rearrangements in follicular lymphoma.Am J Pathol. 2002; 160: 759-763
- Ambivalent role of BCL6 in cell survival and transformation.Oncogene. 2003; 22: 507-516
- A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma.Cancer Cell. 2007; 12: 280-292
- Low-grade follicular lymphoma with t(14;18) presents a homogeneous disease entity otherwise the rest comprises minor groups of heterogeneous disease entities with BCL2 amplification, BCL6 translocation or other gene aberrances.Leukemia. 2005; 19: 1058-1063
- Cytogenetic alterations affecting BCL6 are predominantly found in follicular lymphomas grade 3B with a diffuse large B-cell component.Am J Pathol. 2004; 165: 481-490
- Another look at follicular lymphoma: immunophenotypic and molecular analyses identify distinct follicular lymphoma subgroups.Histopathology. 2013; 62: 860-875
- BCL6 gene amplification/3q27 gain is associated with unique clinicopathological characteristics among follicular lymphoma without BCL2 gene translocation.Mod Pathol. 2008; 21: 973-978
- Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells.Cell. 2016; 167: 405-418
- A distinctive subtype of t(14;18)-negative nodal follicular non-Hodgkin lymphoma characterized by a predominantly diffuse growth pattern and deletions in the chromosomal region 1p36.Blood. 2009; 113: 1053-1061
- High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis.Leukemia. 2012; 26: 559-562
- Pathogenesis of follicular lymphoma.J Clin Invest. 2012; 122: 3424-3431
- Variant t(14;18) in malignant lymphoma: a report of seven cases.Cancer Genet Cytogenet. 2005; 157: 12-17
- A novel fusion 5′AFF3/3′BCL2 originated from a t(2;18)(q11.2;q21.33) translocation in follicular lymphoma.Oncogene. 2008; 27: 6187-6190
- The heterogeneity of follicular lymphomas: from early development to transformation.Virchows Arch. 2016; 468: 127-139
- Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry.Blood. 2002; 99: 409-426
- BCL-2 and other genomic alterations in the prognosis of large-cell lymphoma.N Engl J Med. 1989; 320: 1047-1054
- Cytogenetic abnormalities predict clinical outcome in non-Hodgkin lymphoma.Ann Intern Med. 1988; 108: 14-20
- Prognostic implications of histologic grade and intensity of BCL-2 expression in follicular lymphomas undergoing rituximab-containing therapy.Hum Pathol. 2013; 44: 2529-2535
- Analysis of secondary chromosomal alterations in 165 cases of follicular lymphoma with t(14;18).Genes Chromosom Cancer. 2001; 30: 375-382
- High TNFRSF14 and low BTLA are associated with poor prognosis in follicular lymphoma and in diffuse large B-cell lymphoma transformation.Clin Exp Hematop. 2019; 59: 1-16
- Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis.Cancer Res. 2010; 70: 9166-9174
- Differences between BCL2-break positive and negative follicular lymphoma unraveled by whole-exome sequencing.Leukemia. 2018; 32: 685-693
- Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease.Blood Adv. 2020; 4 (24): 5652-5665
Article info
Publication history
Published online: March 06, 2023
Accepted:
March 2,
2023
Received in revised form:
February 10,
2023
Received:
June 13,
2022
Identification
Copyright
© 2023 Elsevier Inc. All rights reserved.
