title: Immunohistochemical detection of ZAP70 in chronic lymphocytic leukemia predicts immunoglobulin heavy chain gene mutation status and time to progression.
abstract: Zeta-associated protein-70 (ZAP70) expression measured by flow cytometry has been proposed as a surrogate marker of the somatic mutation status of the immunoglobulin heavy chain variable region (IGHV) genes in chronic lymphocytic leukemia. However, attempts to implement this approach in clinical flow cytometry laboratories have been problematic; many commercially available antibodies give unreliable results. Assessment of ZAP70 protein expression by immunohistochemistry in chronic lymphocytic leukemia tissue sections is an easy, alternative approach, although lack of quantitation and subjective interpretation of results are potential pitfalls. In this study, we correlated ZAP70 protein expression, assessed by immunohistochemistry, with ZAP70 messenger RNA (mRNA) transcript expression, assessed by semi-quantitative real-time reverse transcriptase-polymerase chain reaction assay, with the somatic mutation status of the IGHV genes in previously untreated patients with chronic lymphocytic leukemia. Expression of ZAP70 protein and mRNA transcripts correlated strongly (P=8.238 × 10(-12)). Expression of ZAP70 protein and mRNA transcripts also correlated strongly with the somatic mutation status of the IGHV genes (P=0.000071 and P=0.00076, respectively). Further, ZAP70 positivity by immunohistochemistry was associated with an increased risk of progression to therapy requirement (3-year risk 83% vs 31% for ZAP70 negative by immunohistochemistry, P=0.03). These results show that ZAP70 expression assessed by immunohistochemistry is a reliable surrogate marker of the somatic mutation status of the IGHV genes, and predicts time to progression.
authors.affiliation: Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Joan H
authors.initials: JH
authors.lastname: Admirand
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Knoblock
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.forename: Constantine
authors.initials: C
authors.lastname: Tam
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Schlette
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Lynne V
authors.initials: LV
authors.lastname: Abruzzo
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D050438:Genes, Immunoglobulin Heavy Chain; D006801:Humans; D007150:Immunohistochemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012307:Risk Factors; D013781:Texas; D013997:Time Factors; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000032:analysis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human