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Article: A20, ABIN-1/2, and CARD11 mutations and their prognostic value in gastrointestinal diffuse large B-cell lymphoma

TitleA20, ABIN-1/2, and CARD11 mutations and their prognostic value in gastrointestinal diffuse large B-cell lymphoma
Authors
Issue Date2011
PublisherAmerican Association for Cancer Research.
Citation
Clinical Cancer Research, 2011, v. 17 n. 6, p. 1440-1451 How to Cite?
AbstractPurpose: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas with the activated B-cell-like subtype characterized by constitutive NF-kB activation. Activating mutations of CARD11 and inactivating mutations of A20 are frequent events in DLBCL. However, the full extent of genetic alterations in the NF-κB pathway regulators and their potential prognostic value in DLBCL remain to be investigated. We investigated the genetic abnormalities of CARD11, A20, and ABIN-1/2/3 (the A20 binding inhibitor of NF-κB) and their clinicopathologic correlation in gastrointestinal DLBCL. Experimental Design: The somatic mutation and copy number changes of CARD11, A20, and ABIN-1/ 2/3 were investigated in 71 gastrointestinal DLBCLs by PCR/sequencing, and interphase FISH/array comparative genomic hybridization, respectively. The mutations identified were functionally characterized by NF-κB reporter assays and immunoprecipitation experiments. Results: Recurrent somatic mutations were found in CARD11 (10%), A20 (17%), ABIN-1 (4%), and ABIN-2 (3%), but not in ABIN-3. In comparison with the wild-type, all CARD11 mutants were potent NF-κB activators in vitro. On the basis of the destructive nature of the observed mutations, and the findings by reporter assays and immunoprecipitation studies, most if not all of the somatic mutations that were seen in A20, ABIN-1, and ABIN-2 could impair their normal functions. Among these genetic abnormalities, A20 somatic mutation was significantly associated with both poor overall survival and event-free survival. Conclusions: We show further evidence of NF-kB pathway genetic abnormalities in DLBCL, which are potentially valuable in the prognosis and design of future therapeutic strategies. ©2011 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/148637
ISSN
2015 Impact Factor: 8.738
2015 SCImago Journal Rankings: 5.314
ISI Accession Number ID
Funding AgencyGrant Number
Leukemia and Lymphoma Research, UK
Elimination of Leukemia Fund, UK
Lady Tata Memorial Trust
Kay Kendal Leukemia Fund, UK
China Scholarship Council
Funding Information:

The research in M-Q. Du laboratory was supported by grants from Leukemia and Lymphoma Research, UK; the Elimination of Leukemia Fund, UK; the Lady Tata Memorial Trust and the Kay Kendal Leukemia Fund, UK. G. Dong was supported by a fellowship from the China Scholarship Council.

References

 

DC FieldValueLanguage
dc.contributor.authorDong, Gen_US
dc.contributor.authorChanudet, Een_US
dc.contributor.authorZeng, Nen_US
dc.contributor.authorAppert, Aen_US
dc.contributor.authorChen, YWen_US
dc.contributor.authorAu, WYen_US
dc.contributor.authorHamoudi, RAen_US
dc.contributor.authorWatkins, AJen_US
dc.contributor.authorYe, Hen_US
dc.contributor.authorLiu, Hen_US
dc.contributor.authorGao, Zen_US
dc.contributor.authorChuang, SSen_US
dc.contributor.authorSrivastava, Gen_US
dc.contributor.authorDu, MQen_US
dc.date.accessioned2012-05-29T06:14:16Z-
dc.date.available2012-05-29T06:14:16Z-
dc.date.issued2011en_US
dc.identifier.citationClinical Cancer Research, 2011, v. 17 n. 6, p. 1440-1451en_US
dc.identifier.issn1078-0432en_US
dc.identifier.urihttp://hdl.handle.net/10722/148637-
dc.description.abstractPurpose: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas with the activated B-cell-like subtype characterized by constitutive NF-kB activation. Activating mutations of CARD11 and inactivating mutations of A20 are frequent events in DLBCL. However, the full extent of genetic alterations in the NF-κB pathway regulators and their potential prognostic value in DLBCL remain to be investigated. We investigated the genetic abnormalities of CARD11, A20, and ABIN-1/2/3 (the A20 binding inhibitor of NF-κB) and their clinicopathologic correlation in gastrointestinal DLBCL. Experimental Design: The somatic mutation and copy number changes of CARD11, A20, and ABIN-1/ 2/3 were investigated in 71 gastrointestinal DLBCLs by PCR/sequencing, and interphase FISH/array comparative genomic hybridization, respectively. The mutations identified were functionally characterized by NF-κB reporter assays and immunoprecipitation experiments. Results: Recurrent somatic mutations were found in CARD11 (10%), A20 (17%), ABIN-1 (4%), and ABIN-2 (3%), but not in ABIN-3. In comparison with the wild-type, all CARD11 mutants were potent NF-κB activators in vitro. On the basis of the destructive nature of the observed mutations, and the findings by reporter assays and immunoprecipitation studies, most if not all of the somatic mutations that were seen in A20, ABIN-1, and ABIN-2 could impair their normal functions. Among these genetic abnormalities, A20 somatic mutation was significantly associated with both poor overall survival and event-free survival. Conclusions: We show further evidence of NF-kB pathway genetic abnormalities in DLBCL, which are potentially valuable in the prognosis and design of future therapeutic strategies. ©2011 AACR.en_US
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research.-
dc.relation.ispartofClinical Cancer Researchen_US
dc.subject.meshAdaptor Proteins, Signal Transducing - Geneticsen_US
dc.subject.meshCard Signaling Adaptor Proteins - Geneticsen_US
dc.subject.meshChemokine Ccl20 - Geneticsen_US
dc.subject.meshChromosome Aberrationsen_US
dc.subject.meshDna-Binding Proteins - Geneticsen_US
dc.subject.meshGastrointestinal Neoplasms - Geneticsen_US
dc.subject.meshGuanylate Cyclase - Geneticsen_US
dc.subject.meshHumansen_US
dc.subject.meshImmunoprecipitationen_US
dc.subject.meshIn Situ Hybridization, Fluorescenceen_US
dc.subject.meshLymphoma, Large B-Cell, Diffuse - Geneticsen_US
dc.subject.meshMutationen_US
dc.subject.meshNf-Kappa B - Metabolismen_US
dc.subject.meshPrognosisen_US
dc.subject.meshPromoter Regions, Geneticen_US
dc.subject.meshSequence Analysis, Dnaen_US
dc.titleA20, ABIN-1/2, and CARD11 mutations and their prognostic value in gastrointestinal diffuse large B-cell lymphomaen_US
dc.typeArticleen_US
dc.identifier.emailSrivastava, G:gopesh@pathology.hku.hken_US
dc.identifier.authoritySrivastava, G=rp00365en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1158/1078-0432.CCR-10-1859en_US
dc.identifier.pmid21266526-
dc.identifier.scopuseid_2-s2.0-79952730520en_US
dc.identifier.hkuros184386-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79952730520&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume17en_US
dc.identifier.issue6en_US
dc.identifier.spage1440en_US
dc.identifier.epage1451en_US
dc.identifier.isiWOS:000288435300024-
dc.publisher.placeUnited Statesen_US

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