Test Catalog

Test ID: CXLPL    
CXCR4 Mutation Analysis, Somatic, Lymphoplasmacytic Lymphoma/Waldenstrom Macroglobulinemia

Useful For Suggests clinical disorders or settings where the test may be helpful

Prognostication and clinical management of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test is intended to detect gene mutations within the C-terminus end of the CXCR4 gene that are commonly found in association with MYD88 L265P mutations in cases of Lymphoplasmacytic Lymphoma/Waldenstrom Macroglobulinemia (LPL/WM).

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) is a B-cell lymphoma that is characterized by an aberrant accumulation of malignant lymphoplasmacytic cells in the bone marrow, lymph nodes, and spleen. It is a B-cell neoplasm that can exhibit excess production of serum immunoglobulin-M symptoms related to hyperviscosity, tissue filtration, and autoimmune-related pathology. CXCR4 mutations are identified in approximately 30% to 40% of LPL/WM and are almost always in association with MYD88 L265P, which is highly prevalent in this neoplasm. The status of CXCR4 mutations in the context of MYD88 L265P is clinically relevant as important determinants of clinical presentation, overall survival, and therapeutic response to ibrutinib. A MYD88-L265P/CXCR4-WHIM (C-terminus nonsense/frameshift mutations) molecular signature is associated with intermediate to high bone marrow disease burden and serum IgM levels, less adenopathy, and intermediate response to ibrutinib in previously treated patients; a MYD88-L265P/CXCR4-WT (wild type) molecular signature is associated with intermediate bone marrow disease burden and serum IgM levels, more adenopathy, and highest response to ibrutinib in previously treated patients; and the MYD88-WT/CXCR4-WT molecular signature is associated with inferior overall survival, lower response to ibrutinib therapy in previously treated patients, and lower bone marrow disease burden in comparison to those harboring a MYD88-L265 mutation. This test is used to aid in the prognostication and therapeutic management of LPL/WM.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Mutations present or absent in the test region of the CXCR4 gene (NCBI NM_003467.2, GRCh37).

Interpretation Provides information to assist in interpretation of the test results

Mutations detected or not detected. An interpretive report will be issued.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

This test is a targeted assay for the C-terminus end of the CXCR4 gene only. It examines c.898-1059 of the CXCR4 gene (NCBI NM_003467.2 GRCh37) and does not detect variants outside this region. A 1% analytical sensitivity was established at 50 ng DNA input for the hotspot mutations c.1013C->G/A only, which uses BNAclamped Sanger sequencing and DNA that does not meet the established criteria can lead to false-negative results. In the extremely rare event that a rare polymorphism or indel may occur at the Sanger sequencing primer binding sites, in cis, with a c.1013C->G/A, data can yield a failed result. Routine Sanger sequencing is used to interrogate other mutations in the tested region with a 15% to 20% analytical sensitivity. The analytical sensitivity of the assay can be affected by a variety of factors, including biologic availability (ie, tumor burden), fixation of paraffin-embedded specimens, rare polymorphisms or indels at the primer binding sites, or nonspecific PCR interferences.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Hunter ZR, Xu L, Yang G, et al: The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell Lymphomagenesis. Blood 2014;123(11):1637-1646

2. Landgren O, Tageja N: MYD88 and beyond: novel opportunities for diagnosis, prognosis and treatment in Waldenstrom’s Macroglobulinemia. Leukemia 2014;28:1799-1803

3. Poulain S, Roumier C, Venet-Caillault A, et al: Genomic Landscape of CXCR4 Mutations in Waldenstrom Macroglobulinemia. Clin Cancer Res 2016;22(6):1480-1488

4. Roccaro A, Sacco A, Jimenez C, et al: C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood 2014;123(26):4120-4131

5. Schmidt J, Federmann B, Schindler N, et al: MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity. Br J Haematol 2015;169:795-803

6. Treon S, Cao Y, Xu L, et al: Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood 2014;123(18):2791-2796

7. Treon S, Tripsas C, Meid K, et al: Ibrutinib in previously treated Waldenstrom’s Macroglobulinemia. NEJM 2015;372(15):1430-1440

8. Xu L, Hunter ZR, Tsakmaklis N, et al: Clonal architecture of CXCR4 WHIM-like mutations in Waldenstrom Macroglobulinaemia. Br J Haematol 2016;172:735-744

Special Instructions Library of PDFs including pertinent information and forms related to the test