title: MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction.
abstract: By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor κB activity and is present in >90% of Waldenström macroglobulinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin G MGUS (0/9) patients as well as healthy donors (0/40; P < 1.5 × 10(-5) for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P ΔCT and BM disease involvement (r = 0.89, P = .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early oncogenic event in WM pathogenesis.
authors: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Lian
authors: L
authors: Xu
authors: Zachary R
authors: ZR
authors: Hunter
authors: Guang
authors: G
authors: Yang
authors: Yangsheng
authors: Y
authors: Zhou
authors: Yang
authors: Y
authors: Cao
authors: Xia
authors: X
authors: Liu
authors: Enrica
authors: E
authors: Morra
authors: Alessandra
authors: A
authors: Trojani
authors: Antonino
authors: A
authors: Greco
authors: Luca
authors: L
authors: Arcaini
authors: Marzia
authors: M
authors: Varettoni
authors: Maria
authors: M
authors: Varettoni
authors: Jennifer R
authors: JR
authors: Brown
authors: Yu-Tzu
authors: YT
authors: Tai
authors: Kenneth C
authors: KC
authors: Anderson
authors: Nikhil C
authors: NC
authors: Munshi
authors: Christopher J
authors: CJ
authors: Patterson
authors: Robert J
authors: RJ
authors: Manning
authors: Christina K
authors: CK
authors: Tripsas
authors: Neal I
authors: NI
authors: Lindeman
authors: Steven P
authors: SP
authors: Treon
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution / Q000502:physiology; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D007075:Immunoglobulin M / Q000235:genetics / Q000378:metabolism; D007930:Leucine / Q000235:genetics; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011392:Proline / Q000235:genetics; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics*
chemical_list: D007075:Immunoglobulin M; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D011392:Proline; D007930:Leucine