MYD88 (L265P) mutation is associated with an unfavourable outcome of primary central nervous system lymphoma

2016 ◽  
Vol 177 (3) ◽  
pp. 492-494 ◽  
Author(s):  
Keiichiro Hattori ◽  
Mamiko Sakata-Yanagimoto ◽  
Yasushi Okoshi ◽  
Yuki Goshima ◽  
Shintaro Yanagimoto ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Central Nervous System Lymphoma ◽  
Unfavourable Outcome ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

scholarly journals Clinicopathologic correlates of MYD88 L265P mutation and programmed cell death (PD-1) pathway in primary central nervous system lymphoma

2019 ◽  
Vol 60 (12) ◽  
pp. 2880-2889 ◽  
Author(s):  
Tarsheen K. Sethi ◽  
Alexandra E. Kovach ◽  
Natalie S. Grover ◽  
Li-Ching Huang ◽  
Laura A. Lee ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Programmed Cell Death ◽  
Central Nervous System Lymphoma ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

Somatic Mutations Detected in Plasma Cell-Free DNA By Targeted Sequencing: Assessment of Liquid Biopsy in Primary Central Nervous System Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 332-332 ◽  
Author(s):  
Maxime Fontanilles ◽  
Florent Marguet ◽  
Élodie Bohers ◽  
Pierre-Julien Viailly ◽  
Philippe Bertrand ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Somatic Mutation ◽  
Somatic Mutations ◽  
Central Nervous System Lymphoma ◽  
Targeted Sequencing ◽  
Variant Allele Frequency ◽  
Free Dna ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

Abstract Background Primary Central Nervous System Lymphoma (PCNSL) are rare and aggressive primary brain tumors. Histological diagnosis can be difficult at initial stages or at relapse due to deep brain structure involvement. Finding a minimally invasive biomarker aiding the diagnosis remains an unsolved question. Plasma Cell-Free DNA (cfDNA) seems to have shown its diagnostic and prognostic value in nodal Diffuse Large B Cell Lymphomas (DLBCL) [Roschewski et al, Lancet Oncology, 2015; Kurtz et al, Blood, 2015]. Our main objective was to demonstrate that targeted sequencing of cfDNA in plasma at time of diagnosis could identify PCNSL somatic mutations. Methods 30 immuno-competent patients suffering from newly diagnosed PCNSL, without any extranevraxic lesions, were enrolled from 2008 to 2014. Tumor tissues and plasma samples were collected at the time of diagnosis and frozen until use. High throughput sequencing was performed on primitive tumors using a panel of 34 genes relevant to lymphomagenesis, as previously reported [Dubois et al, Oncotarget, 2015; Bohers et al, Haematologica, 2015]. We next performed patient-specific targeted sequencing of identified somatic mutations in cfDNA. The detection sensitivity threshold was set at 1% for all SNVs, except for MYD88 L265P, which was set at 0.1%. The primary endpoint was the proportion of patients having at least one somatic mutation found in the plasma. Results Among 24 available plasmas, 15 patients (63%) had at least one detected somatic mutation in cfDNA. All plasmas had detectable cfDNA (mean concentration 1.6 ng/µL). No correlation was found between tumor volume and cfDNA concentration (R squared coefficient 0.01). Regarding the whole sequenced cohort (n=30) 21 (70%) were classified as nonGC subtype, 8 (27%) as GC subtype and 1 patient (3%) as unclassifiable, according to the Hans algorithm. 29 tumors had at least one somatic mutation, mainly nonsynonymous single nucleotide variants (SNV). The NF-kB pathway was the most affected by mutations: MYD88 (n=23, 77%), PIM1 (n=11, 37%), TNFAIP3 (n=6, 20%), IRF4 (n=3, 10%), CARD11 (n=3, 10%) and PRDM1 (n=3, 10%). Among the 23 tumors harboring a MYD88 mutation, the L265P variant was the most frequent (20 patients, 67%); mean tumor variant allele frequency was 46% [min 8%, max 91%]. One tumor harbored a single MYD88 L265P mutation with no other detectable abnormality. Among patients with both available plasma and a somatic MYD88 L265P mutation in the tumor, 15 patients (88%) had an identifiable L265P variant in cfDNA, with a mean variant allele frequency of 4% [min 0.1%, max 28%]. PIM1 and TNFAIP3 SNVs were also detected in cfDNA for respectively two and one patient. The second most affected pathway was the apoptotic pathway: genes affected by mutations included GNA13 (n=7, 23%), TP53 (n=2, 7%), MYC (n=1, 3%), CDKN2A (n=2, 7%) and BCL2 (n=1, 3%). The B Cell Receptor (BCR) pathway was also affected, mainly due to mutations targeting CD79B (n=10, 33%) and ITPKB (n=3, 10%) mutations. 8 tumors (27%) harbored a dual alteration affecting MYD88 and CD79B. One tumor of the GC subtype had one EZH2 SNV (Y646H), but the mutation was not found in cfDNA. There was no significant difference in overall survival (OS) between patients with and without mutations detected in cfDNA: mean OS 27 months versus 18 months (HR 0.6; IC95% [0.2 - 1.6], p value 0.3). Tumor gene copy number variations were detected in 29/30 patients with either homo or heterozygous deletions or copy gains. CDKN2A/2B deletions were detected in 23 cases (77%). Conclusion To our knowledge this is the first study that provides evidence that somatic mutations can be detected in cfDNA in patients suffering from PCNSL, therefore constituting a minimally invasive tool helping for diagnosis. Further studies are now required to improve prognosis and predictive values of this new promising procedure for PCNSL patient care. Disclosures No relevant conflicts of interest to declare.

MYD88 L265P mutation and CDKN2A loss as early mutational events in primary central nervous system lymphomas.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e14041-e14041
Author(s):  
Michael White ◽  
Priscilla Kaliopi Brastianos ◽  
Tracy Batchelor ◽  
Naema Nayyar ◽  
Corey Gill ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

scholarly journals MYD88 L265P mutation in primary central nervous system lymphoma is associated with better survival: A single centre experience

2021 ◽  
Author(s):  
Olimpia E Curran ◽  
Michael T C Poon ◽  
Louise Gilroy ◽  
Antonia Torgersen ◽  
Colin Smith ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Survival Data ◽  
Cox Regression ◽  
Central Nervous System Lymphoma ◽  
Primary Response ◽  
Current Evidence ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Myd88 L265p Mutation

Abstract Background The Myeloid differentiation primary response gene (MYD88) mutation in primary central nervous system lymphomas (PCNSL) may be associated with unfavourable prognosis, however current evidence remains limited. We aimed to characterise PCNSLs by integration of clinicopathological, molecular, treatment and survival data. Methods We retrospectively identified and validated 57 consecutive patients with PCNSLs according to the 2017 WHO classification of lymphoid neoplasms over 13 years. Formalin-fixed paraffin-embedded tumour samples underwent polymerase chain reaction assay to detect MYD88 mutation. We used Cox regression for survival analysis including age, treatment and MYD88 as covariates. We searched the literature for studies reporting demographics, treatment, MYD88 and survival of PCNSL patients, and incorporated individual-patient data into our analyses. Results The median age was 66 years and 56% were women. All 57 patients had PCNSL of non-germinal centre cell subtype and the majority (81%) received either single or combined therapies. There were 46 deaths observed over the median follow-up of 10 months. MYD88 mutation status was available in 41 patients of which 36 (88%) were mutated. There was an association between MYD88 mutation and better survival in the multivariable model (hazard ratio [HR] 0.277; 95% confidence interval [CI] 0.09-0.83; p=0.023) but not in a univariable model. After incorporating additional 18 patients from the literature, this association was reproducible (HR 0.245, 95% CI 0.09-0.64, p=0.004). Conclusions Adjusting for confounders, MYD88-mutant PCNSL appears to show improved survival. While further validation is warranted, detection of MYD88 mutation will aid identification of patients who may benefit from novel targeted therapies.

scholarly journals MYD88 L265P mutation in primary central nervous system lymphoma is associated with better survival: A single centre experience.

2020 ◽  
Author(s):  
Olimpia E. Curran ◽  
Michael T. C. Poon ◽  
Louise Gilroy ◽  
Antonia Torgersen ◽  
Colin Smith ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Survival Data ◽  
Cox Regression ◽  
Central Nervous System Lymphoma ◽  
Primary Response ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Allele Specific ◽  
Myd88 L265p Mutation

Background: The Myeloid differentiation primary response gene (MYD88) mutation in primary central nervous system lymphomas (PCNSL) may be associated with unfavourable prognosis, however the evidence remains limited. We aimed to comprehensively characterise PCNSLs by integration of clinicopathological, molecular, treatment and survival data. Methods: We retrospectively identified and validated 57 consecutive patients with PCNSLs according to the 2017 WHO classification of lymphoid neoplasms over a 13-year period. Formalin-fixed paraffin-embedded tumour samples underwent real-time allele-specific polymerase chain reaction assay to detect MYD88 mutation. We used multivariable Cox regression for survival analysis including age, treatment, and MYD88 as covariates. We searched the literature for studies reporting demographics, treatment, MYD88 and survival of PCNSL patients, and incorporated individual-patient data into our analyses. Results: The median age was 66 years and 56% were women. All 57 patients had PCNSL of non-germinal centre cell subtype and the majority (81%) received either single or combined therapies. There were 46 deaths observed over the median follow-up of 10 months. MYD88 mutation status was available in 41 patients of which 36 (88%) were mutated. There was an association between MYD88 mutation and better survival in the multivariable model (hazard ratio [HR] 0.34; 95% confidence interval [CI] 0.12-0.95; p=0.039) but not in a univariable model. After incorporating additional 18 patients from the literature, this association was reproducible (HR 0.31, 95% CI 0.13-0.77, p=0.012). Conclusions: Adjusting for confounders, MYD88 mutation is associated with better survival. While further validation is warranted, identification of MYD88 mutation can identify patients who may benefit from novel targeted therapies.

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