TY - JOUR
T1 - Clinical Validation of a CXCR4 Mutation Screening Assay for Waldenstrom Macroglobulinemia
AU - Ballester, Leomar Y.
AU - Loghavi, Sanam
AU - Kanagal-Shamanna, Rashmi
AU - Barkoh, Bedia A.
AU - Lin, Pei
AU - Medeiros, L. Jeffrey
AU - Luthra, Rajyalakshmi
AU - Patel, Keyur P.
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - Mutations in CXCR4 have been identified in ∼29% of patients with Waldenstrom macroglobulinemia having the MYD88L265P mutation. CXCR4 mutations interfere with treatment response to ibrutinib. We designed and validated Sanger sequencing and pyrosequencing assays to detect mutations in CXCR4 in a Clinical Laboratory Improvement Amendments-approved clinical laboratory. We identified CXCR4 mutations in 8 of 33 low grade B-cell lymphomas examined. Objectives Waldenstrom macroglobulinemia (WM) is a B-cell lymphoma characterized by the accumulation of lymphocytes and plasmacytic cells in the bone marrow and by excess production of immunoglobulin M in serum. WM has been closely linked with the MYD88L265P mutation. Whole genome sequencing has identified somatic mutations in the CXCR4 gene in ∼29% of WM cases with MYD88L265P. CXCR4 mutations may interfere with treatment response to ibrutinib. The goal of this study was to design and validate a clinical assay to detect CXCR4 mutations. Methods Thirty-three low-grade B-cell lymphomas with plasmacytic differentiation (23 MYD88L265P and 10 MYD88WT) involving various samples types (fresh and formalin-fixed tissues) formed the study group. We designed and validated Sanger sequencing and pyrosequencing assays to detect mutations in CXCR4 in a Clinical Laboratory Improvement Amendments-approved clinical laboratory. Results We identified 8 cases with CXCR4 mutations, including 5 single nucleotide substitutions (3 resulting in p.S338* and 1 in p.R334*), and 3 insertion/deletions. Seven of 8 CXCR4 mutated cases were also MYD88L265P mutant. Among the single nucleotide substitutions, we identified a novel missense variant (p.L326P) and a previously reported variant (G335S) of uncertain clinical significance. Conclusions We successfully validated a set of clinical assays to detect mutations in CXCR4 mutations in a clinical laboratory.
AB - Mutations in CXCR4 have been identified in ∼29% of patients with Waldenstrom macroglobulinemia having the MYD88L265P mutation. CXCR4 mutations interfere with treatment response to ibrutinib. We designed and validated Sanger sequencing and pyrosequencing assays to detect mutations in CXCR4 in a Clinical Laboratory Improvement Amendments-approved clinical laboratory. We identified CXCR4 mutations in 8 of 33 low grade B-cell lymphomas examined. Objectives Waldenstrom macroglobulinemia (WM) is a B-cell lymphoma characterized by the accumulation of lymphocytes and plasmacytic cells in the bone marrow and by excess production of immunoglobulin M in serum. WM has been closely linked with the MYD88L265P mutation. Whole genome sequencing has identified somatic mutations in the CXCR4 gene in ∼29% of WM cases with MYD88L265P. CXCR4 mutations may interfere with treatment response to ibrutinib. The goal of this study was to design and validate a clinical assay to detect CXCR4 mutations. Methods Thirty-three low-grade B-cell lymphomas with plasmacytic differentiation (23 MYD88L265P and 10 MYD88WT) involving various samples types (fresh and formalin-fixed tissues) formed the study group. We designed and validated Sanger sequencing and pyrosequencing assays to detect mutations in CXCR4 in a Clinical Laboratory Improvement Amendments-approved clinical laboratory. Results We identified 8 cases with CXCR4 mutations, including 5 single nucleotide substitutions (3 resulting in p.S338* and 1 in p.R334*), and 3 insertion/deletions. Seven of 8 CXCR4 mutated cases were also MYD88L265P mutant. Among the single nucleotide substitutions, we identified a novel missense variant (p.L326P) and a previously reported variant (G335S) of uncertain clinical significance. Conclusions We successfully validated a set of clinical assays to detect mutations in CXCR4 mutations in a clinical laboratory.
KW - Ibrutinib
KW - Lymphoplasmacytic lymphoma
KW - MGUS
KW - MYD88
KW - WHIM syndrome
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U2 - 10.1016/j.clml.2016.04.014
DO - 10.1016/j.clml.2016.04.014
M3 - Article
C2 - 27268124
AN - SCOPUS:84971642807
SN - 2152-2650
VL - 16
SP - 395-403.e1
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
IS - 7
ER -