title: MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.
abstract: BACKGROUND
  Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated.
  
  
  METHODS
  We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors.
  
  
  RESULTS
  Among the patients with Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2.
  
  
  CONCLUSIONS
  MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.).
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana–Farber Cancer Institute, M547, 450 Brookline Ave., Boston, MA 02115, USA. steven_treon@dfci.harvard.edu
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.forename: Lian
authors.initials: L
authors.lastname: Xu
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Yangsheng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Patricia
authors.initials: P
authors.lastname: Sheehy
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Manning
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Patterson
authors.forename: Christina
authors.initials: C
authors.lastname: Tripsas
authors.forename: Luca
authors.initials: L
authors.lastname: Arcaini
authors.forename: Geraldine S
authors.initials: GS
authors.lastname: Pinkus
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Aliyah R
authors.initials: AR
authors.lastname: Sohani
authors.forename: Nancy Lee
authors.initials: NL
authors.lastname: Harris
authors.forename: Jason M
authors.initials: JM
authors.lastname: Laramie
authors.forename: Donald A
authors.initials: DA
authors.lastname: Skifter
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Lincoln
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Hunter
mesh_terms: D003937:Diagnosis, Differential; D018450:Disease Progression; D015870:Gene Expression; D015894:Genome, Human; D006801:Humans; D007075:Immunoglobulin M / Q000032:analysis; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D010265:Paraproteinemias / Q000175:diagnosis / Q000276:immunology; D017422:Sequence Analysis, DNA; D008258:Waldenstrom Macroglobulinemia / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology
chemical_list: D007075:Immunoglobulin M; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88