Cell‐free <scp>DNA</scp> analysis for detection of <scp>MYD88L265P</scp> and <scp>CXCR4S338X</scp> mutations in <scp>W</scp>aldenström macroglobulinemia

Demos, Maria; Hunter, Zachary; Liu, Xu; Tsakmaklis, Nicholas; Kofides, Amanda; Munshi, Manit; Liu, Xia; Guerrera, Maria Luisa; Leventoff, Carly; White, Timothy P.; Flynn, Catherine; Meid, Kirsten; Patterson, Christopher J.; Yang, Guang; Branagan, Andrew R.; Sarosiek, Shayna; Castillo, Jorge J.; Treon, Steven P.; Gustine, Joshua

doi:10.1002/ajh.26184

Cited by 8 publications

(6 citation statements)

References 16 publications

(59 reference statements)

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“…This could be related to false positives on ASO-PCR due to MYD88 L265P clonal lymphopoiesis in a subset of patients. Our results could also shed light on some unexpected findings in treated LPL/WM ( 59 , 60 ), which showed that some patients had MYD88 L265P in unselected BM samples but not in CD19-positive sorted cells. Similar observations have been reported in cases with chronic myeloid leukemia; the presence of BCR-ABL1 mRNA in peripheral blood from patients in treatment-free remission was seen predominantly in the B cell compartment and thus did not imply the persistence of multipotent leukemic cells ( 61 ).…”

Section: Discussionsupporting

confidence: 54%

Preneoplastic somatic mutations including MYD88 ^L265P in lymphoplasmacytic lymphoma

et al. 2022

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Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88 . We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88 L265P in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88 L265P is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.

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Section: Discussionsupporting

confidence: 54%

Preneoplastic somatic mutations including MYD88 ^L265P in lymphoplasmacytic lymphoma

et al. 2022

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“…Therefore, we also analysed cfDNA in a small set of cases, following the promising results observed in WM. 21,[32][33][34] We found that ddPCR was able to detect and quantify MYD88 mutation in cfDNA in IgM MGUS and SWM, allowing us to infer correlation with other biomarkers. Regarding CXCR4 mutations in cfDNA, previous reports have been mostly focused on WM samples 21,33 ; while one study using a different sequencing approach reported that two out of nine IgM MGUS patients harboured CXCR4 mutations.…”

Section: Discussionmentioning

confidence: 80%

“…21,[32][33][34] We found that ddPCR was able to detect and quantify MYD88 mutation in cfDNA in IgM MGUS and SWM, allowing us to infer correlation with other biomarkers. Regarding CXCR4 mutations in cfDNA, previous reports have been mostly focused on WM samples 21,33 ; while one study using a different sequencing approach reported that two out of nine IgM MGUS patients harboured CXCR4 mutations. 32 In our study, it has been more difficult to show solid cfDNA data in asymptomatic IgM patients.…”

Section: Discussionmentioning

confidence: 80%

“…Considering that MYD88 testing is based on single BM samples for each patient and that BM disease distribution can be somehow heterogeneous and patchy, it could affect mutation detection. Therefore, we also analysed cfDNA in a small set of cases, following the promising results observed in WM 21,32–34 . We found that ddPCR was able to detect and quantify MYD88 mutation in cfDNA in IgM MGUS and SWM, allowing us to infer correlation with other biomarkers.…”

Section: Discussionmentioning

confidence: 92%

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Prognostic impact of MYD88 and CXCR4 mutations assessed by droplet digital polymerase chain reaction in IgM monoclonal gammopathy of undetermined significance and smouldering Waldenström macroglobulinaemia

et al. 2022

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Summary Waldenström macroglobulinaemia (WM) is characterized by recurrent somatic mutations in MYD88 and CXCR4 genes. However, limitations arise when analysing these mutations in IgM monoclonal gammopathy of undetermined significance (MGUS) or smouldering WM (SWM) given the lower tumour load. Here, we used droplet digital polymerase chain reaction (ddPCR) to analyse MYD88 L265P and CXCR4 S338* mutations (C1013G and C1013A) in unsorted bone marrow (BM) or cell‐free DNA (cfDNA) samples from 101 IgM MGUS and 69 SWM patients. ddPCR was more sensitive to assess MYD88 L265P compared to allele‐specific PCR, especially in IgM MGUS (64% vs 39%). MYD88 mutation burden correlated with other laboratory biomarkers, particularly BM infiltration (r = 0.8; p < 0.001). CXCR4 C1013G was analysed in MYD88‐mutated samples with available genomic DNA and was detected in 19/54 (35%) and 18/42 (43%) IgM MGUS and SWM cases respectively, also showing correlation with BM involvement (r = 0.9; p < 0.001). ddPCR also detected 8 (38%) and 10 (63%) MYD88‐mutated cfDNA samples in IgM MGUS and SWM respectively. Moreover, high BM mutation burden (≥8% MYD88 and ≥2% CXCR4) was associated with an increased risk of progression to symptomatic WM. We show the clinical applicability of ddPCR to assess MYD88 and CXCR4 in IgM MGUS and SWM and provide a molecular‐based risk classification.

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“…The use of digital droplet PCR has shown high concordance with AS‐PCR for the detection of MYD88 L265P 13,14 . Moreover, the detection of MYD88 L265P in cell‐free DNA is feasible in WM patients and may represent a novel tissue for molecular testing 15–18 . These efforts to optimize molecular testing are collectively important to ensure the accurate identification of MYD88 MUT , which impact diagnosis, prognosis, and treatment selection in WM patients 9 …”

Section: As‐pcr Ngs Cd19‐selected Bm Unselected Bm Unselected Bmmentioning

confidence: 99%

Diagnostic Next-generation Sequencing Frequently Fails to Detect MYD88L265P in Waldenström Macroglobulinemia

et al. 2021

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Cell‐free DNA analysis for detection of MYD88^L265P and CXCR4^S338X mutations in Waldenström macroglobulinemia

Cited by 8 publications

References 16 publications

Preneoplastic somatic mutations including MYD88 ^L265P in lymphoplasmacytic lymphoma

Preneoplastic somatic mutations including MYD88 ^L265P in lymphoplasmacytic lymphoma

Prognostic impact of MYD88 and CXCR4 mutations assessed by droplet digital polymerase chain reaction in IgM monoclonal gammopathy of undetermined significance and smouldering Waldenström macroglobulinaemia

Diagnostic Next-generation Sequencing Frequently Fails to Detect MYD88L265P in Waldenström Macroglobulinemia

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Cell‐free DNA analysis for detection of MYD88L265P and CXCR4S338X mutations in Waldenström macroglobulinemia

Cited by 8 publications

References 16 publications

Preneoplastic somatic mutations including MYD88 L265P in lymphoplasmacytic lymphoma

Preneoplastic somatic mutations including MYD88 L265P in lymphoplasmacytic lymphoma

Prognostic impact of MYD88 and CXCR4 mutations assessed by droplet digital polymerase chain reaction in IgM monoclonal gammopathy of undetermined significance and smouldering Waldenström macroglobulinaemia

Diagnostic Next-generation Sequencing Frequently Fails to Detect MYD88L265P in Waldenström Macroglobulinemia

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Cell‐free DNA analysis for detection of MYD88^L265P and CXCR4^S338X mutations in Waldenström macroglobulinemia

Preneoplastic somatic mutations including MYD88 ^L265P in lymphoplasmacytic lymphoma

Preneoplastic somatic mutations including MYD88 ^L265P in lymphoplasmacytic lymphoma