CXCR4 Mutational Analysis
Waldenstrom macroglobulinemia (WM) is a distinct indolent B-cell malignancy that shares many clinical and pathological features with other B-cell lymphomas and multiple myeloma. Immunoglobulin M (IgM) monoclonal gammopathy of unknown significance (MGUS) is a precursor state for WM with approximately 2% of IgM MGUS patients evolving to a B-cell malignancy per year, with most of these individuals progressing to WM. A recurrent somatic mutation, L265P in the MYD88 gene has been reported to occur in over 90% of WM patients.
Chemokine (C-X-C motif) receptor type 4 (CXCR4) mutations have also been identified in ~27% of WM patients. Ninety-eight percent (98%) of the patients with a CXCR4 mutation are also positive for the MYD88L265P mutation. Conversely, ~94% of MYD88-WT patients are also CXCR4-WT. The CXCR4 mutations associated with WM are clustered in the C-terminus of the protein and interfere with normal receptor internalization required to down-regulate CXCR4 mediated signaling. As a result of the mutations, there is an increase in the number of CXCR4 receptors at the cell membrane, leading to increased activation of the signaling pathway. Recent studies show that CXCR4 mutations are associated with resistance to ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor used in the treatment of WM patients.
This assay is available as PCR-based DNA Sanger sequencing of exon 2 of the CXCR4 gene.
The assay is designed to detect mutations in codons 292 to 353 in exon 2 of CXCR4. The lower limit of sensitivity of detection is approximately one mutated cell per five total cells within the sample (20%).
10 mL peripheral blood, 2-5mL bone marrow aspirate, or 5µg purified DNA. Tissue sections may also be utilized for testing purposes, and testing requires formalin-fixed, paraffin embedded tissue blocks or 4-10 unstained tissue sections on glass slides along with 1 H&E-stained section containing adequate amounts of tumor to be analyzed (see above sensitivity), with areas to be tested clearly indicated on the slides/block. Please provide a copy of the corresponding pathology report.
Additional charges may apply for tissue extraction.
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