Molecular markers
MYD88
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Last author update: 25 May 2023
Last staff update: 25 May 2023
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PubMed Search: MYD88 molecular
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Diagrams / tables | Clinical features | Uses by pathologists | Prognostic factors | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Board review style question #1 | Board review style answer #1Cite this page: Chen Wongworawat Y, Fisher KE. MYD88. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/molecularMYD88.html. Accessed December 4th, 2024.
Definition / general
- MYD88 innate immune signal transduction adaptor
- MYD88 gene (NM_002468.5) is located on chromosome 3p22.2 and has 5 exons (NIH: Homo Sapiens MYD88 Innate Immune Signal Transduction Adaptor (MYD88), Transcript Variant 2, mRNA [Accessed 23 May 2023])
Essential features
- Somatic activating mutations in MYD88 are the most frequent molecular alteration in patients with lymphoplasmacytic lymphoma (LPL) and Waldenström macroglobulinemia (WM) and are seen in > 90% of cases (Blood 2014;123:1637, Haematologica 2017;102:2077)
- The most common somatic activating mutation in LPL and WM is the MYD88 c.794T>C, p.Leu265Pro (p.L265P) mutation (Blood 2014;123:1637)
- The presence of a somatic MYD88 p.L265P mutation is a major diagnostic criterion for the diagnosis of LPL and WM
- Activating somatic mutations in MYD88 are also observed in ~50% of IgM monoclonal gammopathy of unknown significance (IgM MGUS), suggesting that MYD88 mutation is an early genetic event in the development of WM (Haematologica 2017;102:2077, Blood 2013;121:2522)
- Activating somatic mutations in MYD88 are also reported in various other B cell neoplasms including diffuse large B cell lymphomas (DLBCL), mucosa associated lymphoid tissue (MALT) lymphoma and chronic lymphocytic leukemia (Blood 2013;121:2051, Blood 2014;123:1637, Leukemia 2017;31:1355)
Terminology
- MYD88 innate immune signal transduction adaptor
- Myeloid differentiation primary response 88
Pathophysiology
- MYD88 encodes a cytosolic adapter protein that plays a central role in the innate and adaptive immune response
- This protein functions as an essential signal transducer in the interleukin 1 and Toll-like receptor signaling pathways
- These pathways regulate the activation of numerous proinflammatory genes (NIH: MYD88 Innate Immune Signal Transduction Adaptor [Accessed 8 March 2023])
- MYD88 p.L265P missense mutation is located in the MYD88 Toll / interleukin 1 receptor (TIR) domain
- The mutation preferentially activates downstream signaling through the Toll-like receptor and interleukin 1 (IL1) receptor signaling (N Engl J Med 2012;367:826)
- Gain of function mutations also activate the downstream transcription complex nuclear factor kappa light chain enhancer of activated B cells (NFkB) to promote cell proliferation and survival (N Engl J Med 2012;367:826)
Diagrams / tables
Images hosted on other servers:
MYD88, NFkB pathway
Clinical features
- Inherited / germline mutations in this gene are associated with immunodeficiency 68 (ID68), an autosomal recessive primary immunodeficiency characterized by severe systemic and invasive bacterial infections beginning in infancy or early childhood (OMIM: Immunodeficiency 68; IMD68 [Accessed 8 March 2023])
- Somatic mutations in this gene are reported in LPL, WM, IgM MGUS, DLBCL, MALT lymphoma and other B cell malignancies
- MYD88 mutations are most prevalent in immune privileged site associated DLBCL (IP DLBCL), presenting in central nervous system (75%) or testis (71%) and are relatively uncommon in nodal (17%) and gastrointestinal tract lymphomas (11%) (Blood Cancer J 2013;3:e139)
- MYD88 mutation was more frequently detected in activated B cell-like (ABC) than germinal center B cell-like (GCB) subtype DLBCL (Sci Rep 2017;7:1785)
- MYD88 mutation has much lower prevalence in other small B cell lymphomas; for example, ~2% in chronic lymphocytic leukemia (CLL) (Leukemia 2017;31:1355)
Uses by pathologists
- Somatic activating mutations in MYD88 are the most frequent molecular alteration in patients with LPL and WM and are seen in > 90% of cases
- The vast majority of somatic activating mutations are the MYD88 c.794T>C p.Leu265Pro (p.L265P) missense mutation (Blood 2014;123:1637, Haematologica 2017;102:2077)
- Presence of a somatic MYD88 p.L265P mutation is a major diagnostic criterion for the diagnosis of LPL and WM; however, the absence of a somatic MYD88 p.L265P mutation does not exclude the diagnosis of WM or LPL
- MYD88 p.M232T variant has been recently described in WM, whereas the MYD88 p.V217F and p.S219C variants have been previously reported in DLBCL (N Engl J Med 2015;373:584, Nature 2011;470:115)
Prognostic factors
- In a multicenter trial of ibrutinib monotherapy in previously treated WM patients, patients with MYD88 mutations alone had a more favorable prognosis than those with MYD88 / CXCR4 comutated or wild type MYD88 disease (J Clin Oncol 2021;39:565)
- Presence of CXCR4 mutations in MYD88 mutated LPL may be associated with higher disease activity (Br J Haematol 2015;169:795)
Molecular / cytogenetics description
- Detection of MYD88 activating mutations requires sequencing based methods such as Sanger sequencing, next generation sequencing or pyrosequencing
Molecular / cytogenetics images
Contributed by Kevin E. Fisher, M.D., Ph.D.
MYD88, p.L265P, NGS, IGV
Sample pathology report
- Lymph node biopsy, targeted next generation sequencing:
- MYD88 p.L265P missense mutation detected (see comment)
- Comment: Targeted next generation sequencing of the lymph node biopsy revealed a p.Leu265pro missense variant in the MYD88 (MYD88 innate immune signal transduction adaptor) gene at a variant allele fraction (VAF) of 13.6%. MYD88 encodes a cytosolic adapter protein that plays a central role in the innate and adaptive immune response. This protein functions as an essential signal transducer in the interleukin 1 and Toll-like receptor signaling pathways and regulate the activation of numerous proinflammatory genes. MYD88 activating mutations, such as the MYD88 p.L265P missense mutation, are seen in > 90% of patients with lymphoplasmacytic lymphoma and Waldenström macroglobulinemia. In the appropriate clinical and histopathologic context, the presence of a MYD88 activating mutation is considered a major diagnostic criterion for these entities. Clinical and histopathologic correlation is recommended.
Board review style question #1
Next generation sequencing was performed on a bone marrow aspirate as part of a diagnostic work up for anemia, fatigue and neuropathies. The results are shown in the image above. This finding is considered a diagnostic marker for which of the following?
- Chronic neutrophilic leukemia
- Essential thrombocythemia
- Plasma cell myeloma
- Systemic mastocytosis
- Waldenström macroglobulinemia
Board review style answer #1
E. Waldenström macroglobulinemia. This Integrative Genomics Viewer image provides a visual representation of a single nucleotide variant (T>C) in a leucine within the MYD88 gene. MYD88 activating mutations, such as the MYD88 p.L265P, are seen in > 90% of patients with lymphoplasmacytic lymphoma and Waldenström macroglobulinemia. The presence of a MYD88 activating mutation is a major diagnostic criterion for these entities.
Answer A is incorrect because CSF3R activating mutations are seen in > 60% of patients with chronic neutrophilic leukemia and the presence of a CSF3R activating mutation is a major diagnostic criterion for this entity. Answer B is incorrect because mutations in JAK2, MPL or CALR are diagnostic markers for essential thrombocythemia. Answer C is incorrect because multiple (plasma cell) myeloma affects many signaling pathways, the most common being MAPK pathways including KRAS, NRAS and BRAF in ~40% of cases. Answer D is incorrect because the KIT p.D816V mutation is present in the vast majority of typical indolent systemic mastocytosis cases.
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Reference: MYD88
Answer A is incorrect because CSF3R activating mutations are seen in > 60% of patients with chronic neutrophilic leukemia and the presence of a CSF3R activating mutation is a major diagnostic criterion for this entity. Answer B is incorrect because mutations in JAK2, MPL or CALR are diagnostic markers for essential thrombocythemia. Answer C is incorrect because multiple (plasma cell) myeloma affects many signaling pathways, the most common being MAPK pathways including KRAS, NRAS and BRAF in ~40% of cases. Answer D is incorrect because the KIT p.D816V mutation is present in the vast majority of typical indolent systemic mastocytosis cases.
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Reference: MYD88
