N-terminus DUX4-immunohistochemistry is a reliable methodology for the diagnosis of DUX4-fused B-lymphoblastic leukemia/lymphoma (N-terminus DUX4 IHC for DUX4-fused B-ALL)
(2022) In Genes Chromosomes and Cancer 61(8). p.449-458- Abstract
B-lymphoblastic leukemia/lymphoma (B-ALL) is the most common pediatric malignancy and the most commonly diagnosed adult lymphoblastic leukemia. Recent advances have broadened the spectrum of B-ALL, with DUX4 gene fusions implicated in a subclass occurring in adolescents and young adults and harboring a favorable prognosis. DUX4 fusions have been challenging to identify. We aimed to determine whether expression of the DUX4 oncoprotein, as detected by targeted immunohistochemistry, might serve as a surrogate for molecular detection of DUX4 fusions in B-ALL. A cohort of investigational B-ALLs was generated with enrichment for DUX4 fusions by the inclusion of cases with characteristic demographic features and immunophenotypic properties.... (More)
B-lymphoblastic leukemia/lymphoma (B-ALL) is the most common pediatric malignancy and the most commonly diagnosed adult lymphoblastic leukemia. Recent advances have broadened the spectrum of B-ALL, with DUX4 gene fusions implicated in a subclass occurring in adolescents and young adults and harboring a favorable prognosis. DUX4 fusions have been challenging to identify. We aimed to determine whether expression of the DUX4 oncoprotein, as detected by targeted immunohistochemistry, might serve as a surrogate for molecular detection of DUX4 fusions in B-ALL. A cohort of investigational B-ALLs was generated with enrichment for DUX4 fusions by the inclusion of cases with characteristic demographic features and immunophenotypic properties. B-ALLs with mutually exclusive cytogenetics were collected. Immunohistochemical staining by a monoclonal antibody raised against the N-terminus of the DUX4 protein was performed. N-DUX4 immunohistochemistry demonstrated strong, crisp nuclear staining in blasts of seven investigational cases, six of which had nucleic acid material available for molecular evaluation. Five of these cases demonstrated RNA-seq DUX4-fusion positivity. One N-DUX4 immunohistochemistry positive case lacked a definitive DUX4-fusion by RNA-seq, though demonstrated a gene expression profile characteristic of DUX4-rearranged B-ALLs, a CD2+ immunophenotype, and a lack of staining by C-terminus DUX4 antibody immunohistochemistry. At least 83.3% [5/6] positive predictive value. N-DUX4 immunohistochemistry was negative in blasts of three RNA-seq DUX4-fusion-negative cases (3/3; 100% negative predictive value). B-ALLs with mutually exclusive cytogenetic profiles were all N-DUX4 negative (0/10, specificity 100%). N-DUX4 immunohistochemistry is reliable for the distinction of DUX4-rearranged B-ALLs from other B-ALLs. We recommend its use for subclassification of B-ALLs in adolescents and young adults and in B-ALLs that remain “not otherwise specified.”.
(Less)
- author
- Siegele, Bradford J. ; Stemmer-Rachamimov, Anat O. ; Lilljebjorn, Henrik LU ; Fioretos, Thoas LU ; Winters, Amanda C. ; Dal Cin, Paola ; Treece, Amy ; Gaskell, Alisa and Nardi, Valentina
- organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Adolescent and young adult, B-lymphoblastic leukemia, DUX4, immunohistochemistry
- in
- Genes Chromosomes and Cancer
- volume
- 61
- issue
- 8
- pages
- 449 - 458
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- pmid:35218117
- scopus:85125677545
- ISSN
- 1045-2257
- DOI
- 10.1002/gcc.23033
- language
- English
- LU publication?
- yes
- id
- bc10533f-e28f-4fa0-8494-d0d98679ab83
- date added to LUP
- 2022-04-26 12:03:04
- date last changed
- 2024-09-19 21:19:12
@article{bc10533f-e28f-4fa0-8494-d0d98679ab83, abstract = {{<p>B-lymphoblastic leukemia/lymphoma (B-ALL) is the most common pediatric malignancy and the most commonly diagnosed adult lymphoblastic leukemia. Recent advances have broadened the spectrum of B-ALL, with DUX4 gene fusions implicated in a subclass occurring in adolescents and young adults and harboring a favorable prognosis. DUX4 fusions have been challenging to identify. We aimed to determine whether expression of the DUX4 oncoprotein, as detected by targeted immunohistochemistry, might serve as a surrogate for molecular detection of DUX4 fusions in B-ALL. A cohort of investigational B-ALLs was generated with enrichment for DUX4 fusions by the inclusion of cases with characteristic demographic features and immunophenotypic properties. B-ALLs with mutually exclusive cytogenetics were collected. Immunohistochemical staining by a monoclonal antibody raised against the N-terminus of the DUX4 protein was performed. N-DUX4 immunohistochemistry demonstrated strong, crisp nuclear staining in blasts of seven investigational cases, six of which had nucleic acid material available for molecular evaluation. Five of these cases demonstrated RNA-seq DUX4-fusion positivity. One N-DUX4 immunohistochemistry positive case lacked a definitive DUX4-fusion by RNA-seq, though demonstrated a gene expression profile characteristic of DUX4-rearranged B-ALLs, a CD2+ immunophenotype, and a lack of staining by C-terminus DUX4 antibody immunohistochemistry. At least 83.3% [5/6] positive predictive value. N-DUX4 immunohistochemistry was negative in blasts of three RNA-seq DUX4-fusion-negative cases (3/3; 100% negative predictive value). B-ALLs with mutually exclusive cytogenetic profiles were all N-DUX4 negative (0/10, specificity 100%). N-DUX4 immunohistochemistry is reliable for the distinction of DUX4-rearranged B-ALLs from other B-ALLs. We recommend its use for subclassification of B-ALLs in adolescents and young adults and in B-ALLs that remain “not otherwise specified.”.</p>}}, author = {{Siegele, Bradford J. and Stemmer-Rachamimov, Anat O. and Lilljebjorn, Henrik and Fioretos, Thoas and Winters, Amanda C. and Dal Cin, Paola and Treece, Amy and Gaskell, Alisa and Nardi, Valentina}}, issn = {{1045-2257}}, keywords = {{Adolescent and young adult; B-lymphoblastic leukemia; DUX4; immunohistochemistry}}, language = {{eng}}, number = {{8}}, pages = {{449--458}}, publisher = {{John Wiley & Sons Inc.}}, series = {{Genes Chromosomes and Cancer}}, title = {{N-terminus DUX4-immunohistochemistry is a reliable methodology for the diagnosis of DUX4-fused B-lymphoblastic leukemia/lymphoma (N-terminus DUX4 IHC for DUX4-fused B-ALL)}}, url = {{http://dx.doi.org/10.1002/gcc.23033}}, doi = {{10.1002/gcc.23033}}, volume = {{61}}, year = {{2022}}, }