Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia.

Abstract

CXCR4(WHIM) somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4(WHIM) mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4(WHIM) mutations (CXCR4(S338X C>A and C>G) ) in WM. The AS-PCR assays detected CXCR4(S338X) mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4(S338X) mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4(WHIM) mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis. The presence of multiple CXCR4(WHIM) mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.

• Authors: Lian Xu, Zachary R Hunter, Nicholas Tsakmaklis, Yang Cao, Guang Yang, Jie Chen, Xia Liu, Sandra Kanan, Jorge J Castillo, Yu-Tzu Tai, James L Zehnder, Jennifer R Brown, Ruben D Carrasco, Ranjana Advani, Jean M Sabile, Kimon Argyropoulos, M Lia Palomba, Enrica Morra, Alessandra Trojani, Antonino Greco, Alessandra Tedeschi, Marzia Varettoni, Luca Arcaini, Nikhil M Munshi, Kenneth C Anderson, Steven P Treon
• Journal: British journal of haematology (Br J Haematol) Vol. 172 Issue 5 Pg. 735-44 (Mar 2016) ISSN: 1365-2141 [Electronic] England
• PMID: 26659815 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 John Wiley & Sons Ltd.

Chemical References

• CXCR4 protein, human
• Immunoglobulin M
• MYD88 protein, human
• Myeloid Differentiation Factor 88
• Receptors, CXCR4

Topics

• Adult
• Aged
• Aged, 80 and over
• Amino Acid Substitution
• Female
• Genomic Instability
• Humans
• Immunoglobulin M (blood)
• Lymphoma, B-Cell, Marginal Zone (genetics)
• Male
• Middle Aged
• Monoclonal Gammopathy of Undetermined Significance (genetics)
• Mutation
• Myeloid Differentiation Factor 88 (genetics)
• Polymerase Chain Reaction (methods)
• Receptors, CXCR4 (genetics)
• Sequence Analysis, DNA (methods)
• Waldenstrom Macroglobulinemia (genetics)