Recurrent mutations of <scp><i>CD79B</i></scp> and <scp><i>MYD88</i></scp> are the hallmark of primary central nervous system lymphomas

Nakamura, Taishi; Tateishi, Kensuke; Niwa, Tomohiro; Matsushita, Yuko; Tamura, Kaoru; Kinoshita, Manabu; Tanaka, Kazuhiro; Fukushima, Shintaro; Takami, Hirokazu; Arita, Hideyuki; Kubo, Atsuhiko; Shuto, Takashi; Ohno, Masasuke; Miyakita, Yasuji; Kocialkowski, Sylvia; Sasayama, Takashi; Hashimoto, Naoya; Maehara, Taketoshi; Shibui, Soichiro; Ushijima, Toshikazu; Kawahara, Nobutaka; Narita, Yoshitaka; Ichimura, Koichi

doi:10.1111/nan.12259

Cited by 193 publications

(178 citation statements)

References 27 publications

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“…Twenty-nine studies have reported that the frequency of MYD88 L265P mutation in 2285 DLBCL patients except for central nervous system (CNS) and testicular lymphomas was 16.5% (95% CI: 11.9–22.6%) 2, 3, 6, 7, 9–11, 13, 16–22, 24, 25, 27, 28, 30, 31, 33–39, 41 . Thirteen 4, 5, 8, 9, 12, 14, 15, 18, 21, 23, 26, 32, 40 and four 8, 9, 21, 29 studies reported the prevalence of MYD88 L265P mutation in 378 CNS and 88 testicular DLBCL patients. The MYD88 L265P mutation in the CNS and testis were detected in 59.8% (95% CI: 42.2–75.2%) and 77.1% (95% CI: 67.1–84.7%), respectively.…”

Section: Resultsmentioning

confidence: 99%

Clinicopathologic significance of MYD88 L265P mutation in diffuse large B-cell lymphoma: a meta-analysis

Lee

Jeong

Choi

et al. 2017

Sci Rep

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The precise clinicopathologic significance of myeloid differentiation primary response gene (MYD88) L265P mutation in diffuse large B-cell lymphomas (DLBCLs) remains elusive. To investigate the frequency and clinicopathologic significance of the MYD88 L265P mutation in DLBCLs, we conducted a meta-analysis of 40 published studies on 2736 DLBCL patients. We collected relevant published research findings identified using the PubMed and Embase databases. The effect sizes of outcome parameters were calculated using a random-effects model. In this meta-analysis, the MYD88 L265P mutation in DLBCL showed a significant difference according to tumor sites. The overall incidence of the MYD88 L265P mutation in DLBCLs, excluding the central nervous system and testicular DLBCLs, was 16.5%. Notably, the MYD88 L265P mutation rates of CNS and testicular DLBCL patients were 60% and 77%, respectively. Interestingly, the MYD88 L265P mutation was more frequently detected in activated B-cell-like (ABC) or non-germinal center B-cell-like (GCB) than GCB subtype (OR = 3.414, p < 0.001). The MYD88 L265P mutation was significantly associated with old age and poor overall survival, but not with sex and clinical stage. This pooled analysis demonstrates that the MYD88 L265P mutation is significantly associated with the tumor sites and molecular subtypes in DLBCL patients.Myeloid differentiation primary response gene (MYD88) is an adaptor protein that activates the nuclear transcription factor κB (NF-κB) signaling through most of the Toll-like receptors (TLRs) 1 . An L265P mutation, a change from leucine (CTC) to proline (CCG), in the MYD88 Toll/interleukin (IL)-1 receptor domain, recruits MYD88 protien to the cytoplasmic tail of TLRs to form an active complex. The complex promotes NF-κB and Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) signaling 1 .Recently, many investigators have reported that the prevalence of MYD88 L265P mutation ranges from 0% to 94% in different series of diffuse large B-cell lymphoma (DLBCL) patients 2-41 . However, since the MYD88 L265P mutation occurs at various frequencies of DLBCL, a general consensus on clinicopathologic implications has not been reached. DLBCL is a heterogeneous non-Hodgkin's lymphoma mainly comprising molecular subtypes such as germinal center B-cell-like (GCB) and activated B-cell-like (ABC) types 42 . Several studies have suggested that the frequency of MYD88 L265P mutation may vary depending on the tumor site or molecular subtype of DLBCL 2,8,21,24,30,41 , but individual studies with different designs hinder clear conclusions. Furthermore, the clinicopathologic significance of the MYD88 L265P mutation in each DLBCL patient was controversial.To address these controversies, we conducted a meta-analysis to examine the frequency of MYD88 L265P mutation and the relationship between this mutation and the clinicopathologic parameters of DLBCL patients. ResultsPrevalence of MYD88 L265P mutation in diffuse large B-cell lymphoma. On pooled analysis of 40 studies, includin...

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Section: Resultsmentioning

confidence: 99%

Clinicopathologic significance of MYD88 L265P mutation in diffuse large B-cell lymphoma: a meta-analysis

Lee

Jeong

Choi

et al. 2017

Sci Rep

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“…The frequent utilization of V H 4-34 in ABC DLBCL cases is consistent with previous work demonstrating an enrichment for V H 4-34 among DLBCL cases classified as "non-GCB" by immunostaining (20). Primary central nervous system lymphoma (PCNSL) is a type of DLBCL that has an ABC phenotype (38) and acquires several of the pathognomonic mutations of ABC DLBCL (39)(40)(41)(42). V H 4-34 is used in 55% of PCNSL cases, an enrichment that suggests that this V H segment confers a selective advantage in PCNSL, as in nodal ABC DLBCL.…”

Section: Discussionmentioning

confidence: 99%

Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

Young

Schmitz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

159

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The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) relies on chronic active B-cell receptor (BCR) signaling. BCR pathway inhibitors induce remissions in a subset of ABC DLBCL patients. BCR microclusters on the surface of ABC cells resemble those generated following antigen engagement of normal B cells. We speculated that binding of lymphoma BCRs to self-antigens initiates and maintains chronic active BCR signaling in ABC DLBCL. To assess whether antigenic engagement of the BCR is required for the ongoing survival of ABC cells, we developed isogenic ABC cells that differed solely with respect to the IgH V region of their BCRs. In competitive assays with wild-type cells, substitution of a heterologous V region impaired the survival of three ABC lines. The viability of one V H 4-34 + ABC line and the ability of its BCR to bind to its own cell surface depended on V region residues that mediate the intrinsic autoreactivity of V H 4-34 to self-glycoproteins. The BCR of another ABC line reacted with self-antigens in apoptotic debris, and the survival of a third ABC line was sustained by reactivity of its BCR to an idiotypic epitope in its own V region. Hence, a diverse set of self-antigens is responsible for maintaining the malignant survival of ABC DLBCL cells. IgH V regions used by the BCRs of ABC DLBCL biopsy samples varied in their ability to sustain survival of these ABC lines, suggesting a screening procedure to identify patients who might benefit from BCR pathway inhibition.lymphoma | cancer biology | B-cell receptor

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“…Recent studies indicated that a high frequency (>75%) of MYD88 L265P mutations (an adaptor protein mediating toll-like receptor and interleukin-1 signaling) in the DLBCL subtype of PCNSL may be an initiator of disease. Additionally, most MYD88 L265P-positive patients have CD79B or CARD11 mutations (B cell receptor signaling pathway)282930. In addition, the constitutive activation of the nuclear factor (NF)- κB pathway is a hallmark of B cell PCNSL31.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid IL-10 and IL-10/IL-6 as Accurate Diagnostic Biomarkers for Primary Central Nervous System Large B-cell Lymphoma

Song

Zhang

et al. 2016

Sci Rep

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Early diagnosis of primary central nervous system lymphoma (PCNSL) represents a challenge, and cerebrospinal fluid (CSF) cytokines may be diagnostic biomarkers for PCNSL. We used an electrochemiluminescence immunoassay to measure interleukin (IL)-10, IL-6, IL-8 and tumor necrosis factor α (TNF-α) in the CSF of 22 B cell PCNSL patients and 80 patients with other CNS diseases. CSF IL-10 was significantly higher in PCNSL patients than in the control group (median 74.7 pg/ml vs < 5.0 pg/ml, P < 0.000). Using a CSF IL-10 cutoff value of 8.2 pg/ml, the diagnostic sensitivity and specificity were 95.5% and 96.1%, respectively (AUC, 0.957; 95% CI, 0.901–1.000). For a CSF IL-10/IL-6 cutoff value of 0.72, the sensitivity was 95.5%, and the specificity was 100.0% (AUC, 0.976; 95% CI, 0.929–1.000). An increased CSF IL-10 level at diagnosis and post-treatment was associated with poor Progression free survival (PFS) for patients with PCNSL (P = 0.0181 and P = 0.0002, respectively). A low diagnostic value for PCNSL was found with CSF IL-8 or TNF-α. In conclusion, increased CSF IL-10 was a reliable diagnostic biomarker for large B cell PCNSL, and an IL-10/IL-6 ratio facilitates differentiation from other conditions, especially a CNS infection.

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Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas

Cited by 193 publications

References 27 publications

Clinicopathologic significance of MYD88 L265P mutation in diffuse large B-cell lymphoma: a meta-analysis

Clinicopathologic significance of MYD88 L265P mutation in diffuse large B-cell lymphoma: a meta-analysis

Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

Cerebrospinal Fluid IL-10 and IL-10/IL-6 as Accurate Diagnostic Biomarkers for Primary Central Nervous System Large B-cell Lymphoma

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