1p Loss Research Articles

Abstract 2458: Integrated proteogenomic characterization of clear cell renal cell carcinoma

Abstract Clear cell renal cell carcinoma (ccRCC) is the most predominant histology of renal cancer, representing 75% of all cases and accounting for the majority of associated deaths. Towards understanding the underlying molecular alterations that can drive renal oncogenesis, The Cancer Genome Atlas (TCGA) has performed extensive genomic and transcriptomic profiling, and comparative analyses. To gain insight into the impact of genomic alterations on the functional modules that drive ccRCC tumorigenesis, we leveraged comprehensive proteogenomic characterization of 110 ccRCC tumors and 84 corresponding normal adjacent tissue (NAT) samples. Pairing state-of-the-art mass spectrometry based proteomic and phosphoproteomic strategies with the comprehensive genomic analysis, we integrated global and phosphoproteomic measurements with genomic and transcriptomic data to elucidate the dysregulated cellular mechanism resulting from genomic alterations. Arm-level loss of 3p, involving genes VHL, SETD2, BAP1 and PBRM1 is a frequent event in ccRCC and investigation of chromosomal number variations (CNV), mutations, and methylation profiles of these genes, revealed a unique pattern of BAP1 regulated proteins relative to the other 3p loci genes. Comparative protein profiling of ccRCC tumors and NATs identified pathways associated with immune response and glycolysis to be regulated in ccRCC tumors, however correlating mRNA and protein revealed a non-linear relationship in cellular processes including Warburg Effect-related metabolism and protein translation. Employing unbiased consensus clustering identified three proteomic subtypes of ccRCC, discriminated by differential abundance of proteins involved in adaptive immune response, innate immunity, ribosome activity, and metabolic processes. Further evidence of tumor heterogeneity was observed in the phosphoproteome, with phosphopeptide co-expression modeling generating phospho-signaling modules that overlapped with global protein processes (i.e. adaptive and innate immunity), as well pathways only detected at the phosphoproteomic level (i.e. Notch signaling and DNA repair). The fact that ccRCC tumors are highly immunogenic prompted us to explore the degree of immune infiltration in our cohort. We deconvoluted immune, stromal, and microenvironment cell gene signatures, identifying 60 cell types in our cohort, and three immune-based subtypes of ccRCC: Inflamed, Immune-excluded, and Immune desert. These immune subtypes displayed unique patterns of PD-1, PD-L1, and CTLA4 expression, and could be discriminated by the up-regulation of distinct protein pathways including interferon-γ, HIF1, and EMT. Our results integrated multi-level “omics” analyses to provide greater depth and expand our understanding of ccRCC biology, while identifying novel proteomic, phosphoproteomic, and immune ccRCC subtypes for personalized, precision-based care. Citation Format: David J. Clark, The CPTAC Consortium. Integrated proteogenomic characterization of clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2458.

Genomic evolution of uveal melanoma arising in ocular melanocytosis

Ocular melanocytosis is the most important predisposing condition for the eye cancer uveal melanoma (UM). Here, we present a patient who developed UM arising within ocular melanocytosis who was treated with enucleation (eye removal), which provided an invaluable opportunity to interrogate both the UM and adjacent uveal tissue containing the melanocytosis using whole-exome and deep-targeted sequencing. This analysis revealed a clonal PLCB4 mutation in the melanocytosis, confirming that this is indeed a neoplastic condition and explaining why it predisposes to UM. This mutation was present in 100% of analyzed UM cells, indicating that a PLCB4-mutant cell gave rise to the UM. The earliest aberrations specific to the tumor were loss of Chromosomes 1p, 3, and 9p, which were present in virtually all tumor cells. A mutation in BAP1 arose later on the other copy of Chromosome 3 in a tumor subclone, followed by a gain of Chromosome 8q. These findings provide a mechanistic explanation for the well-known clinical association between ocular melanocytosis and UM by showing that this predisposing condition introduces the first “hit” and thereby increases the stochastic likelihood of acquiring further aberrations leading to UM.

Subgroup-specific prognostic signaling and metabolic pathways in pediatric medulloblastoma

BackgroundUsing a pathway-focused approach, we aimed to provide a subgroup-specific basis for finding novel therapeutic strategies and further refinement of the risk stratification in pediatric medulloblastoma.MethodBased on genome-wide Cox regression and Gene Set Enrichment Analysis, we investigated prognosis-related signaling pathways and core genes in pediatric medulloblastoma subgroups using 530 patient data from Medulloblastoma Advanced Genomic International Consortium (MAGIC) project. We further examined the relationship between expression of the prognostic core genes and frequent chromosome aberrations using broad range copy number change data.ResultsIn SHH subgroup, relatively high expression of the core genes involved in p53, PLK1, FOXM1, and Aurora B signaling pathways are associated with poor prognosis, and their average expression synergistically increases with co-occurrence of losses of 17p, 14q, or 10q, or gain of 17q. In Group 3, in addition to high MYC expression, relatively elevated expression of PDGFRA, IGF1R, and FGF2 and their downstream genes in PI3K/AKT and MAPK/ERK pathways are related to poor survival outcome, and their average expression is increased with the presence of isochromosome 17q [i(17q)] and synergistically down-regulated with simultaneous losses of 16p, 8q, or 4q. In Group 4, up-regulation of the genes encoding various immune receptors and those involved in NOTCH, NF-κB, PI3K/AKT, or RHOA signaling pathways are associated with worse prognosis. Additionally, the expressions of Notch genes correlate with those of the prognostic immune receptors. Besides the Group 4 patients with previously known prognostic aberration, loss of chromosome 11, those with loss of 8q but without i(17q) show excellent survival outcomes and low average expression of the prognostic core genes whereas those harboring 10q loss, 1q gain, or 12q gain accompanied by i(17q) show bad outcomes. Finally, several metabolic pathways known to be reprogrammed in cancer cells are detected as prognostic pathways including glutamate metabolism in SHH subgroup, pentose phosphate pathway and TCA cycle in Group 3, and folate-mediated one carbon-metabolism in Group 4.ConclusionsThe results underscore several subgroup-specific pathways for potential therapeutic interventions: SHH-GLI-FOXM1 pathway in SHH subgroup, receptor tyrosine kinases and their downstream pathways in Group 3, and immune and inflammatory pathways in Group 4.

Molecular cytogenetic analyses of patients with plasma cell myeloma in Tolna and Baranya counties in Hungary

Introduction: Plasma cell myeloma is a hematological malignancy with heterogeneous genomic landscape and diverse clinical course. Recurrent chromosomal and subchromosomal aberrations commonly occur in this entity and are associated with the pathogenesis and progression of the disease. The identification of these alterations aids genetic characterization, classification and prognostication of patients. Aim: Molecular cytogenetic investigations of plasma cell myeloma patients treated at the University of Pécs Clinical Center and János Balassa County Hospital of Tolna County, Szekszárd, between 2005 and 2018 were evaluated in our study. Method: 231 patients were screened for genetic aberrations using fluorescence in situ hybridization. Translocations involving the immunoglobulin heavy chain gene, losses of 1p and 17p chromosome arms, gains of 1q chromosome arm and unbalanced aberrations of chromosome 13 were investigated. Losses and gains of 1p, 1q, 5q, 12p, 13q, 16q and 17p chromosome arms were analyzed using multiplex ligation-dependent probe amplification in 42 patients. During the investigated period, 116 bone marrow karyotyping was also performed. Results: In total, 233 genetic aberrations were identified using our targeted approaches; the frequency of specific aberrations correlated with data of the recent literature. Concordance of results gained by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification was 96.2% by analyzing the same chromosome arms. The latter technique revealed 21 additional genetic aberrations in 16/42 patient samples (38%) as compared to fluorescence in situ hybridization. Conclusions: Our results suggest that the combined application of the two molecular cytogenetic methods may facilitate a more detailed characterization of genetic aberrations of plasma cell myeloma patients in Hungary. Orv Hetil. 2019; 160(24): 944-951.

PB2016 RESULTS OF TREATMENT PATIENTS OF MANTLE CELL LYMPHOMA DEPENDING ON THE MUTATIONAL STATUS OF THE TP53 GENE

Background:According to a retrospective study published data in 2017 by the Nordic MCL group, in multivariable analyses, only mutation TP53 showed independent prognostic impact. The median OS for the TP53‐mutated cases was 1.8 years, median PFS was 0.9 years.Aims:To assess the incidence of TP53 gene mutation and survival in pts with MCL during of prospective trial MCL‐RUS‐2016.Methods:A total 25 pts were enrolled in prospective study MCL‐RUS‐2016 between 2016 to 2019 years. The median age was 52 years (range, 33 to 71 years). Seven pts (28%) were over the age of 60 years. Male:female = 15:10. In all pts the Ann Arbor stage was 4. Among 25 pts in depend pretreatment MIPI score, 36%, 48% and 16%, respectively, were considered as being at low, intermediate and high risk. Seven (28%)of 25 pts had blastoid MCL. Mutation of the TP53 gene determined using by Sanger sequencing of the coding region (exons 1(2)‐11) was present in 4 (16%) pts (TP53mut). Another 21 pts (84%) had wild type mutational status (TP53 wt). Complex karyotype (CK) was indentified in 8 (32%) pts. Three pts had the mutation of p53 and CK. Deletion of 17p was present in 4 (16%) pts, but only 3 of 4 cases with 17p loss displayed TP53 mutation.Results:Eighteen pts (TP53 wt) reseived 4 cycles of alternating of rituximab, bendamustine, cytarabine (R‐BAC) and rituximab, high dose cytarabine 12 g/m2 (R‐HA), followed by stem cell mobilization and ASCT. MRD was not detected in all 18 pts at the end of therapy. Eighteen pts achieved and remain in complete remission and 3 pts continue on treatment. The median follow‐up time was 5 months after ASCT (range, 1‐17 months). Pts with MCL, who have TP53 mutations, had a worse prognosis. Two pts with TP53 mutation in our study died for progression disease. Two pts, who underwent allo‐HCT from non‐relative HLA‐matched donors, is a alive in CR, with the time of observation three and twenty‐seven months.Summary/Conclusion:The regimens R‐BAC/R‐HA was well tolerated with a manageable safety profile. Allogeneic hematopoietic cell transplantation is only curative treatment for MCL with TP53 gene mutation.

A gene signature of response to radiotherapy in patients with grade II-III oligodendrogliomas.

2041 Background: Grade II and III Oligodendroglioma associate mutations of isocitrate deshydrogenase 1 or 2 genes and the whole-arm chromosomal loss of 1p and 19q and have a better prognosis than other gliomas. However, even if the preferred treatment consists of a combination of radiotherapy (RT) and chemotherapy, some patients will less respond to this treatment and will relapse faster , in part because of an heterogeneity in the response to RT. In the aim to identify factors of response to RT, we analyzed clinical and molecular data of patients with grade II-III oligodendroglioma exclusively treated with RT in the POLA cohort. Methods: Gene expression profiles on Affymetrix expression arrays of patients from the POLA cohort with co-deleted 1p/19q grade II/II gliomas treated by exclusive RT were used to identify a gene expression set predictive of radiation sensitivity. The primary endpoint was the progression free survival (PFS), defined as the time from treatment start until progression or death. A supervised approach with penalized regression was applied to select most informative predictors, and then a risk score was created based on the linear predictor given by the multivariable model. Results: Forty-five patients corresponded to the study criteria, with a median age at diagnosis of 45 (range 23- 64). The supervised approach allowed identifying a three-gene prognostic set including Semaphorin -3C (SEMA3C), Neuronal Pentraxin 2 (NPTX2 ) and the Metabotropic Glutamate Receptor 5 (GRM5), involved in proliferation, migration and inflammation. The risk score associated to these three genes was statistically associated to PFS (HR = 2.72, p = 0.00005) and remains significant when adjusted on clinical covariates age at diagnosis, necrosis, endothelial proliferation and type of surgery (complete, partial or subtotal surgery) (HRadj = 2.36, p = 0.001). Conclusions: We report an independent three genes SEMA3C-NPTX2-GRM5 risk score signature of response to radiotherapy in patients with oligodendroglioma, which highlights the heterogeneous response in this reputed good prognosis population. This signature could help in determining the adapted treatment as well as potential new targets to address.

Predictors of differential response to induction therapy in high-risk neuroblastoma: A report from the Children's Oncology Group (COG)

BackgroundInduction chemotherapy plays an important role in the management of patients with high-risk neuroblastoma. Predictors of response to induction therapy are largely lacking. We sought to describe clinical and biological features associated with induction response. MethodsPatients from four consecutive COG high-risk trials were included. Response was evaluated by the 1993 International Neuroblastoma Response Criteria. The primary end-point was end-induction partial response (PR) or better. Univariate analyses were performed to compare response as a function of clinical or biologic predictors. A multivariate logistic regression model using significant predictors from univariate analyses was constructed to model PR or better. ResultsThe analytic cohort included 1242 patients. End-induction response ≥PR was significantly associated with higher event-free and overall survival. Baseline factors associated with ≥PR included age <18 months (87.4% with ≥PR vs. 78.7% if older; p = 0.0103), International Neuroblastoma Staging System non-stage 4 (89.0% vs. 78.4% if stage 4; p = 0.0016), MYCN amplification (85.5% vs. 77.1% if non-amplified; p = 0.0006), 1p loss of heterozygosity (LOH; 85.6% vs. 76.0% if no LOH; p = 0.0085), no 11q LOH (84.8% vs. 70.9% if 11q LOH; p = 0.0004) and high mitosis-karyorrhexis index (MKI; 84.5% vs. 77.5% if low-intermediate MKI; p = 0.0098). On multivariable analysis (n = 407), the absence of 11q LOH was the only factor that remained significantly associated with ≥PR (odds ratio: 1.962 vs. 11q LOH; 95% confidence interval 1.104–3.487; p = 0.0216). ConclusionsImproved end-induction response in high-risk neuroblastoma is associated with longer survival. Patients with 11q LOH are less likely to respond to induction therapies and should be prioritised for novel approaches in future trials.

Genomic landscape of allelic imbalance in premalignant atypical adenomatous hyperplasias of the lung.

BackgroundGenomic investigation of atypical adenomatous hyperplasia (AAH), the only known precursor lesion to lung adenocarcinomas (LUAD), presents challenges due to the low mutant cell fractions. This necessitates sensitive methods for detection of chromosomal aberrations to better study the role of critical alterations in early lung cancer pathogenesis and the progression from AAH to LUAD.MethodsWe applied a sensitive haplotype-based statistical technique to detect chromosomal alterations leading to allelic imbalance (AI) from genotype array profiling of 48 matched normal lung parenchyma, AAH and tumor tissues from 16 stage-I LUAD patients. To gain insights into shared developmental trajectories among tissues, we performed phylogenetic analyses and integrated our results with point mutation data, highlighting significantly-mutated driver genes in LUAD pathogenesis.FindingsAI was detected in nine AAHs (56%). Six cases exhibited recurrent loss of 17p. AI and the enrichment of 17p events were predominantly identified in patients with smoking history. Among the nine AAH tissues with detected AI, seven exhibited evidence for shared chromosomal aberrations with matched LUAD specimens, including losses harboring tumor suppressors on 17p, 8p, 9p, 9q, 19p, and gains encompassing oncogenes on 8q, 12p and 1q.InterpretationChromosomal aberrations, particularly 17p loss, appear to play critical roles early in AAH pathogenesis. Genomic instability in AAH, as well as truncal chromosomal aberrations shared with LUAD, provide evidence for mutation accumulation and are suggestive of a cancerized field contributing to the clonal selection and expansion of these premalignant lesions.FundSupported in part by Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150079 (PS and HK), NIH grant R01HG005859 (PS) and The University of Texas MD Anderson Cancer Center Core Support Grant.

IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.

Natural history of multiple myeloma with de novo del(17p)

We compared the outcomes of 310 patients with newly diagnosed multiple myeloma with del(17p) detected by FISH to patients with high-risk translocations (HRT) (n = 79) and standard-risk (SR) cytogenetics (n = 541). The median progression-free survival (PFS) following initial therapy for the three groups was 21.1, 22, and 30.1 months, respectively (P = 0.437- del(17p) vs. HRT); the median overall survival (OS) was 47.3, 79.1, and 109.8 months, respectively, (P = 0.007- del(17p) vs. HRT). PFS and OS for patients with relative loss of 17p (n = 21) were comparable to other patients with del(17p). The PFS was similar between the del(17p) and HRT groups when stratified for age, ISS stage or treatment. The OS of del(17p) and HRT groups were similar in presence of advanced age, ISS III stage or if patients did not receive a proteasome-inhibitor containing induction. ISS III stage, high LDH and HRT, but not the percentage of cells with del(17p) predicted shorter OS in patients with del(17p). The median OS for low (ISS I, normal LDH and no HRT), intermediate (neither low nor high-risk) and high-risk (ISS III and either elevated LDH or coexistent HRT) groups among del(17p) patients were 96.2, 45.4, and 22.8 months, respectively, allowing further risk stratification.

Abstract P2-05-02: Age-related genetic and epigenetic changes in estrogen-receptor positive breast cancer

Abstract Background: Age is the main risk factor for developing breast cancer (BC) in women. The increase in incidence with age is dominated by estrogen receptor positive (ER+) BC despite the &amp;gt;90% reduction of estrogen levels during menopause and later life. Recent models suggest the lifetime risk of BC is correlated with the number of stem cell divisions with random mutations arising during each division and driving cancer development. However, only two genes are mutated in more than 20% of BC while several recurrent copy number alterations (CNAs) occur in more than 50%. New models of age-related risk factors need to be developed that incorporate mutations, CNAs, epigenetics, and other biological factors. As data of this type is limited in normal breast tissue, factors correlated with age of diagnosis in ER+ BC were identified to understand which variables changed with age and might impact risk of developing BC. Methods: In silico analysis of public databases was used to identify factors in ER+ primary BC and normal adjacent tissue (NT) that are correlated with age of diagnosis including DNA mutations, CNAs, DNA methylation and gene/protein expression (TCGA n=599ER+,113NT; METABRIC n=1435ER+,144NT). Results: DNA mutations accumulated with age in ER+ BC with the median mutation count below 28 in primary tumors diagnosis in patients &amp;lt;50yr and rising to more than 43 in patients &amp;gt;80yr. However, the two most frequently mutated genes (PIK3CA and TP53) showed no significant correlation with age. As previously reported, GATA3 mutation rate was nearly twice as high in younger patients (&amp;lt;50yr=0.25,&amp;gt;80yr=0.12). There was little evidence of a general accumulation of CNAs with age, but there were higher rates of gain in 16p (&amp;lt;50yr=0.42,&amp;gt;80yr=0.51) and loss of 1p (&amp;lt;50yr=0.18,&amp;gt;80yr=0.37) in older patients and lower rates of loss in 6q (&amp;lt;50yr=0.34,&amp;gt;80yr=0.24). The most significant correlations with age related to ESR1 including expression of ESR1 mRNA (rho=0.39,P=1.2e-23 Spearman), ERα protein (rho=0.35,P=1.7e-15 Spearman), and demethylation of ESR1 promoter (rho=-0.36,P=1.6e-13 Spearman). The levels of the activated form of ERα (pS118) also correlated with age but to a much lesser extent than total ERα (rho=0.12,P=0.01 Spearman). Demethylation and expression of ESR1 were highly correlated (rho=-0.50,P&amp;lt;1e-16 Spearman). Analysis of data from NT revealed correlation of age of diagnosis, expression of ESR1 (rho=0.34,P=0.001 Spearman) and demethylation of the ESR1 promoter (rho=-0.22,P=0.03 Spearman) but not with ERα expression (rho=0.32,P=0.19 Spearman) although only 19 NT had protein data. Conclusions: Analysis of DNA mutations and CNAs fit previous theoretical models with both the result of stochastic processes. In these models, the low impact on fitness from individual mutations allows the accumulation over time while the high fitness costs of CNAs prevent accumulation and are likely acquired in a single catastrophic event. The ability of ER+ BC to progress in the presence of very low postmenopausal estrogen levels may be partly explained by demethylation leading to higher ESR1 expression and maintenance of ERα activation. In theory, changes in expression and demethylation can be targeted to reduce the age-related increase in risk for developing BC. Citation Format: Schuster EF, Dowsett M. Age-related genetic and epigenetic changes in estrogen-receptor positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-05-02.

Genome-wide methylation profiling and copy number analysis in atypical fibroxanthomas and pleomorphic dermal sarcomas indicate a similar molecular phenotype

BackgroundAtypical fibroxanthomas (AFX) and pleomorphic dermal sarcomas (PDS) are lesions of the skin with overlapping histologic features and unspecific molecular traits. PDS behaves aggressive compared to AFX. Thus, a precise delineation, although challenging in some instances, is relevant.MethodsWe examined the value of DNA-methylation profiling and copy number analysis for separating these tumors. DNA-methylation data were generated from 17 AFX and 15 PDS using the Illumina EPIC array. These were compared with DNA-methylation data generated from 196 tumors encompassing potential histologic mimics like cutaneous squamous carcinomas (cSCC; n = 19), basal cell carcinomas (n = 10), melanoma metastases originating from the skin (n = 11), leiomyosarcomas (n = 11), angiosarcomas of the skin and soft tissue (n = 11), malignant peripheral nerve sheath tumors (n = 19), dermatofibrosarcomas protuberans (n = 13), extraskeletal myxoid chondrosarcomas (n = 9), myxoid liposarcomas (n = 14), schwannomas (n = 10), neurofibromas (n = 21), alveolar (n = 19) and embryonal (n = 17) rhabdomyosarcomas as well as undifferentiated pleomorphic sarcomas (n = 12).ResultsDNA-methylation profiling did not separate AFX from PDS. The DNA-methylation profiles of the other cases, however, were distinct from AFX/PDS. They reliably assigned to subtype-specific DNA-methylation clusters, although overlap occurred between some AFX/PDS and cSCC. Copy number profiling revealed alterations in a similar frequency and distribution between AFX and PDS. They involved losses of 9p (22/32) and 13q (25/32). Gains frequently involved 8q (8/32). Notably, a homozygous deletion of CDKN2A was more frequent in PDS (6/15) than in AFX (2/17), whereas amplifications were non-recurrent and overall rare (5/32).ConclusionsOur findings support the concept that AFX and PDS belong to a common tumor spectrum. We could demonstrate the diagnostic value of DNA-methylation profiling to delineating AFX/PDS from potential mimics. However, the assessment of certain histologic features remains crucial for separating PDS from AFX.

Biomarkers in tumors of the central nervous system - a review.

Until recently, diagnostics of brain tumors were almost solely based on morphology and immunohistochemical stainings for relatively unspecific lineage markers. Although certain molecular markers have been known for longer than a decade (combined loss of chromosome 1p and 19q in oligodendrogliomas), molecular biomarkers were not included in the WHO scheme until 2016. Now, the classification of diffuse gliomas rests on an integration of morphology and molecular results. Also, for many other central nervous system tumor entities, specific diagnostic, prognostic and predictive biomarkers have been detected and continue to emerge. Previously, we considered brain tumors with similar histology to represent a single disease entity. We now realize that histologically identical tumors might show alterations in different molecular pathways, and often represent separate diseases with different natural history and response to treatment. Hence, knowledge about specific biomarkers is of great importance for individualized treatment and follow-up. In this paper we review the biomarkers that we currently use in the diagnostic work-up of brain tumors.

Efficacy of Lenalidomide and Bortezomib for Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) Relapsing after Allogeneic Stem Cell Transplantation

Introduction: AML and MDS are advanced myeloid malignancies more common among older adults and generally associated with poor outcomes. Allogeneic hematopoietic cell transplantation (HCT) may cure a proportion of affected patients, but disease relapse remains common and is associated with dismal survival. High doses of lenalidomide may modulate graft-vs-leukemia (GvL) effects, and have shown encouraging responses for relapsed AML. Bortezomib may also augment GvL and potentiate the effect of other chemotherapeutics. We conducted a phase I study of escalating doses of bortezomib added to high-dose lenalidomide in patients with AML and MDS, who had relapsed following HCT.Methods: We enrolled patients aged ≥ 18 years, with AML or MDS, relapsing after HCT in a ‘3+3‘ dose-escalation study. Patients with grade ≥3 GVHD, or chronic GVHD requiring >20mg/d of prednisone were excluded. Patients otherwise had to be off immunosuppressive therapy for 2 weeks. Lenalidomide 50mg/d was administered on days 1-21 of 28-day induction cycles. On days 2, 5, 9, and 12, subcutaneous bortezomib was administered at escalating dose levels: 0.7mg/m2, 1.0mg/m2, and 1.3mg/m2. Patients could receive up to two cycles of induction. After reaching the maximally tolerated dose (MTD), 9 patients were enrolled at the recommended phase II dose (RP2D) of bortezomib 1.3mg/m2.Dose limiting toxicities (DLTs) included G4 peripheral neuropathy, G3+ aGVHD, moderate/severe cGVHD, non-resolving G3/4 non-hematologic toxicities, and the inability to receive at least 50% of both drugs during induction. The DLT period spanned up to 2 induction cycles, but could be 1 cycle if a patient entered complete remission (CR) or complete remission with incomplete count recovery (CRi) after the first cycle. Response to induction was the best response after up to two cycles of induction and was assessed in those patients treated at the MTD/RP2D. Donor lymphocyte infusions (DLI) were allowed after induction per the treating physician.Results: A total of 21 patients were enrolled, with a median age of 66 years at study entry (range 23-74). The patients were predominately male (62%) and white (86%), while 2 patients (10%) identified as of Hispanic ethnicity. The majority had AML (19/21), with 10 of the AML patients having disease arising from prior CMML (1), MDS (7), or MPN (2). Three patients had del(5q); 2 patients had loss of 17p and 2 patients had complex cytogenetics. Three patients were enrolled at bortezomib dose levels of 0.7mg/m2 and 1.0mg/m2; at dose level 3, one patient experienced a DLT for receiving < 50% of doses and the cohort was expanded to 6 total patients. An additional 9 expansion patients were then treated at this dose level for a total of 15 patients treated with lenalidomide 50mg and bortezomib 1.3mg/m2. During dose expansion, grade 4 toxicities attributed to study drug included grade 4 neutropenia (n=5), thrombocytopenia (n=3), and febrile neutropenia (n=1), consistent with what was seen during dose escalation. Across all cohorts (n=21), 4 patients achieved CR/CRi.Of the 15 patients treated at the MTD/RP2D, 4 patients had progressive disease after the first induction cycle, and 2 patients stopped therapy during induction cycle 2. A total of 9 patients completed both induction cycles. Of the 15 patients treated at the RP2D, 3 achieved a CR/CRi (20%, 90%CI 5.7-44.0%). Another 2 patients had stable disease. One additional patient achieved a CR in the first dose cohort (Figure 1). Chimerism during treatment tracked with disease response; one patient with persistent low chimerism achieved CRi and received DLI as well (patient 3, who also harbored a TP53 mutation). A total of 3/13 patients tested harbored TP53 mutations; 2/3 achieved CRi while the third (patient 2) came off treatment during induction.Conclusions: Lenalidomide may be safely combined with bortezomib in patients with AML and MDS relapsing after HCT, with an encouraging rate of complete remission (20%) in this poor risk population. Overall toxicities with this regimen were manageable, and largely related to cytopenias. Of note, 2 of the 4 CR/CRi responses on the trial were in patients with TP53-mutated disease, suggesting that this regimen should be further evaluated in this high-risk population, and combination with donor lymphocyte infusion may also merit investigation in larger studies. DisclosuresBrunner:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding. Rosenblatt:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Amrein:Takeda: Research Funding. Chen:Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Fathi:Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding.

CKS1B/CDKN2C Copy Number Ratio : A New Predictor of Survival in Transplant- and Non Transplant-Eligible Multiple Myeloma Patients

BACKGROUNDCurrent molecular risk stratification of multiple myeloma (MM), based on the presence of t(4 ;14) and 17p deletion, cannot fully explain treatment outcome heterogeneity, as other features also predict prognosis. About 30% of genetic events map to chromosome 1 : most upregulated genes to 1q and most downregulated ones to 1p. CKS1B gains on 1q21 and CDKN2C loss on 1p32, both favoring cell cycle progression, portended impaired outcome in many but not all studies. Based on their recurrence and considering their functional convergence, we hypothesized CKS1B/CDKN2C copy number ratio to be a risk factor fitter than each aberration alone.METHODSThis single-center retrospective study, enrolled 104 newly diagnosed adult patients aged ≥18 years, 48 transplant-eligible and 56 not. All patients were routinely tested for CKS1B and CDKN2C and treated according to consensus guidelines. Data were collected from 2012 to May 31, 2018. For each subject, we calculated a FISH-based ratio by CKS1B on CDKN2C copy number : it was equal to 1 with no change in copy number and >1 in case of CKS1B gains, CDKN2C loss or both. In patients with CDKN2C biallelic loss, the ratio was not equal to 0, but to CKS1B copy number, as functional consequence should prevail over arithmetic result. We, then, analyzed separately the impact of CKS1B gains, CDKN2C loss and CKS1B/CDKN2C ratio on PFS and OS.RESULTSIn the transplant subgroup, the median follow-up was 22.9 (1.4-71.9) months. By FISH analysis, 15 patients had variable gains of CKS1B, 6 monoallelic and 1 biallelic CDKN2C loss ; CKS1B/CNKN2C copy number ratio was ≥1.5 in 17, ≥2 in 9 and ≥3 in 2. ROC curves evaluating the relevance of the ratio were statistically significant for PFS (p=0.008) and OS (p=0.049). Median PFS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss and ratio ≥1.5 was 21.6 (1.4-68.4), 24.8 (vs 41.5 with no CKS1B gains), 28.7 (vs 37.7 with no 1p deletion) and 25 (vs 42 with normal ratio) months, respectively. By Kaplan-Meier log-rank analyses, PFS was significantly impaired by CKS1B gains (p=0.014) and ratio ≥1.5 (p=0.007), but not by CDKN2C loss (p=0.339). Median OS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss and ratio ≥1.5 was 22.9 (1.4-71.9), 24.2 (vs 64.2 with no CKS1B gains), 44.9 (vs 54.8 with no 1p deletion) and 32 (vs 64 with normal ratio) months, respectively. By Kaplan-Meier log-rank analyses, OS was also significantly impaired by CKS1B gains (p=0.001) and ratio ≥1.5 (p=0.004), but not CDKN2C loss (p=0.339). In multivariate analyses, parameters negatively influencing PFS were age >65 years (p=0.005), CKS1B gains (p=0.001), ratio ≥1.5 (p=0.006) and ISS3 status (p=0.019) ; factors unfavorably affecting OS were age >65 years (p=0.044), ratio ≥1.5 (p=0.049) and non secretory status (p=0.018), but not CKS1B gains (p=0.174).In the non transplant subgroup, the median follow-up was 26.4 (0.2-87.3) months. By FISH analysis 30 patients had variable gains of CKS1B and 10 hemizygous loss of CDKN2C ; CKS1B/CDKN2C ratio was ≥1.5 in 34, ≥2 in 21 and ≥3 in 7. ROC curves evaluating the relevance of the ratio showed only a trend toward statistical significance for PFS (p=0.065), but not for OS (p=0.137). Median PFS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss, ratio ≥2 and ≥3 was 17.5 (0.2-79.9), 20.9 (vs 26.7 with no CKS1B gains), 15.9 (vs 24.9 with no CDKN2C loss), 16.6 (vs 26.9 for ratio <2) and 11.1 (vs 25.6 for ratio <3) months, respectively. In Kaplan-Meier log-rank analyses, PFS was significantly impaired by ratio ≥3 (p=0.000), but not by CKS1B gains (p=0.204) or CDKN2C loss (p=0.273). Median OS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss, ratio ≥2 and ≥3 was 26.4 (0.2-87.3), 34 (vs 40 with no CKS1B gains), 24 (vs 43.6 with no 1p loss), 31.2 (vs 44.6 with ratio <2) and 13 (vs 45.2 with ratio <3) months, respectively. By Kaplan-Meier log-rank analyses, OS was also negatively affected by ratio ≥3 (p<0.0001), but not by CKS1B gains (p=0.476) or CDKN2C loss (p=0.207). In multivariate analyses, factors negatively impacting PFS were platelet count <150 G/L (p=0.020) and ratio ≥3 (p=0.031) ; parameters unfavorably affecting OS were bone marrow plasma cells ≥60% (p=0.018) and ratio ≥3 (p=0.026).CONCLUSIONSEven with few patients, these results provide proof of the concept of CKS1B/CDKN2C ratio as an outcome predictor. Of note, the ratio indicated worse post-transplant PFS and OS in patients over 65 years. DisclosuresNo relevant conflicts of interest to declare.

Outcomes, Causes of Discontinuation and Mutation Profile of Patients with Mantle Cell Lymphoma Who Progressed on Acalabrutinib

Introduction: Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved for treatment of relapsed patients (pts) with mantle cell lymphoma. We have reported previously that ibrutinib refractory MCL pts have poor survival. However, outcomes, causes of discontinuation, management and the genomic landscape of MCL in pts who discontinued acalabrutinib are rarely reported. Method: We reviewed charts from all MCL pts treated with single agent acalabrutinib (n=28) in the relapsed setting and identified 15 pts who discontinued acalabrutinib and who are described in this analysis. Outcome after discontinuing acalabrutinib is reported. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed on 10 tumor specimens and 5 matched germline samples collected from 9 pts whose MCL progressed on acalabrutinib; among these pts 4 tumors were collected at baseline and 6 were collected after disease progression. One patient had sufficient DNAs available for both time points (baseline and progression). Results: The median duration on treatment with acalabrutinib was 6.5 months (1 to 29 months) and the median number of cycles of acalabrutinib treatment was 6 (range, 1-30). Seven pts had complete remission (CR) as their best response on acalabrutinib, 5 were primary refractory and 3 achieved partial remission. In 12 pts (80%) acalabrutinib was discontinued due to disease progression (2 pts transformed from classic to blastoid and pleomorphic type at progression) and 3 pts were discontinued due to intolerance (one for fatigue and idiopathic encephalopathy, one due to unrelated severe aortic stenosis and another for cytopenias secondary to therapy related myelodysplasia; all three pts were in CR). Nine pts had classic and 3 pts each had blastoid or pleomorphic features before starting acalabrutinib. Overall, median Ki-67 expression was 50% (range, 5-100) and all pts had high a MIPI score. The median number of prior treatments was 1 (range, 1-3); all chemo-immunotherapy (10 pts were previously treated with rituximab-hyper-CVAD) and none with ibrutinib. Two pts who transformed on acalabrutinib received acalabrutinib for a median duration of 12 months (range, 8-16.5). Median follow up after discontinuation was 27 months and the median survival was 25 months (26 months for progression and 1.5 months for intolerance; p Recurrently mutated genes in these tumors included ATM (6/10; 60%), TP53 (4/10; 40%), KMT2C (3/10), MYCN (2/10), NOTCH1 (2/10), NOTCH3 (2/10), and MEF2B (2/10) (Fig. 1B). We did not detect any mutation or copy number alterations in BTK, PLCG2, TRAF2/3 and MYD88 that have been reported previously to be associated with ibrutinib resistance. Compared to tumors at baseline, ATM was mutated at a higher frequency in samples at progression (67% vs. 50%; p=NS). To investigate the mutation evolution on acalabrutinib treatment, mutation profiles, particularly the mutation variant allelic fractions (VAFs), were compared between the baseline and progression samples from pt-1 (Fig. 1C). Mutation of MYCN, MEF2B, ATM, and NOTCH1 were identified in both tumors at similar VAFs, whereas mutation of CARD11 (two mutations), NLRC5 and B2M were detected only at progression. In pt-1, both the NLRC5 and β2M mutations acquired at disease progression were truncating, suggesting loss-of-function alterations. Copy number analysis reveals frequent whole-genome doubling and intensive copy number alterations in all tumors, including recurrent losses of chromosome 9p, 17p, and chromosome 13, indicating chromosomal instability as a driver of disease progression. Conclusion: Patients who progress on acalabrutinib have a poor outcome, and newer therapies are required for their treatment. In this small cohort, we observed non-BTK mutations associated with acalabrutinib resistance and disease progression. Disclosures Nastoupil:Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Merck: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Honoraria, Research Funding; Karus: Research Funding; Novartis: Honoraria; Juno: Honoraria. Neelapu:Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Unum Therapeutics: Membership on an entity9s Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity9s Board of Directors or advisory committees. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Wang:Acerta Pharma: Honoraria, Research Funding; MoreHealth: Consultancy; AstraZeneca: Consultancy, Research Funding; Kite Pharma: Research Funding; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Impact of Acquired Del(17p) in Patients with Multiple Myeloma

Introduction Del(17p) detected by fluorescence in situ hybridisation (FISH) of bone marrow plasma cells (BMPCs) is an adverse prognostic factor in patients with multiple myeloma (MM). While the natural history and prognostic factors in patients with del (17p) detected at diagnosis have been studied, the outcomes of patients who acquire del (17p) later in their course are not known. We aimed to define the outcomes of MM patients who acquire del(17p). Methods We reviewed the Dysproteinemia database at Mayo Clinic, MN to identify 80 patients with MM who had their first FISH test negative for del (17p), but acquired del(17p) later in the course of the disease. Sixty (75%) patients had their first FISH within 6 months (mo) of diagnosis; 20 (25%) patients had their first FISH more than 6 mo after diagnosis of MM. Del(17p) included del(17p13.1) and/or monosomy 17. We identified 2 control patients for each case, who were diagnosed during the same time period, but did not demonstrate del (17p) at any time during follow-up. Results Characteristics of patients at acquisition of del(17p) are shown in Table 1. Of these, 76 patients had relapsed and/or refractory MM; in 4 patients, del (17p) was detected after having attained a response to prior therapy. Seventy (87.5%) patients had del (17p13.1); 5 (6.3%) patients had monosomy 17; 1 (1.2%) patient had both del (17p13.1) and monosomy 17. Four (5.0%) patients had relative loss of 17p. High-risk translocations (HRT) [t(4;14), t(14;16) and t(14;20)] were present in 14 (17.5%) patients. The percentage of PCs with del(17p) were available in 75 patients. The median percentage of PCs with del(17p) was 76 (range, 9-100). Sixty two (77.5%) patients received exclusively chemotherapy as subsequent treatment; stem cell transplant (SCT) was part of the next treatment in 16 (20%) patients (allogeneic SCT in 1). Among 71 evaluable patients, ≥very good partial response and ≥partial response were attained in 24 (33.8%) and 35 (49.2%) patients respectively. The median progression free survival (PFS) from detection of del (17p) was 5.7 mo (95% CI, 3.5-7.8); overall survival (OS) was 18.2 mo (CI, 13.1-27.5). From a comparable time point, the OS for 160 controls was 56.2 mo (CI, 37.1-75.3) (P We performed univariable analysis with variables at detection of del(17p) such as age ≥65 vs. 2 vs. ≤2 mg/dL, BMPC% ≥50 vs. Conclusion The prognosis of patients who acquire del (17p) is poor with OS of 6.5 years against 9 years from diagnosis in patients who do not acquire del (17p). This was valid across prognostic sub-groups. High PC proliferative rate was the only factor which impacted OS once patients acquired del(17p). Disclosures Kapoor:Celgene: Research Funding; Takeda: Research Funding. Gertz:Research to Practice: Consultancy; Teva: Consultancy; Ionis: Honoraria; annexon: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Apellis: Consultancy; Medscape: Consultancy; Amgen: Consultancy; janssen: Consultancy; celgene: Consultancy. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kumar:AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity9s Board of Directors or advisory committees; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity9s Board of Directors or advisory committees; AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding.

Clinical and Genomic Characteristics in De Novo Blastoid/Pleomorphic (dnMCL) and Transformed Blastoid/Pleomorphic (t-MCL) Mantle Cell Lymphoma (MCL) in the Ibrutinib Era: Comprehensive Analysis of 168 Patients

Clinical and Genomic Characteristics in De Novo Blastoid/Pleomorphic (dnMCL) and Transformed Blastoid/Pleomorphic (t-MCL) Mantle Cell Lymphoma (MCL) in the Ibrutinib Era: Comprehensive Analysis of 168 Patients

Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial.

SummaryBackgroundMost children with medulloblastoma fall within the standard-risk clinical disease group defined by absence of high-risk features (metastatic disease, large-cell/anaplastic histology, and MYC amplification), which includes 50–60% of patients and has a 5-year event-free survival of 75–85%. Within standard-risk medulloblastoma, patients in the WNT subgroup are established as having a favourable prognosis; however, outcome prediction for the remaining majority of patients is imprecise. We sought to identify novel prognostic biomarkers to enable improved risk-adapted therapies.MethodsThe HIT-SIOP PNET 4 trial recruited 338 patients aged 4–21 years with medulloblastoma between Jan 1, 2001, and Dec 31, 2006, in 120 treatment institutions in seven European countries to investigate hyperfractionated radiotherapy versus standard radiotherapy. In this retrospective analysis, we assessed the remaining tumour samples from patients in the HIT-SIOP PNET 4 trial (n=136). We assessed the clinical behaviour of the molecularly defined WNT and SHH subgroups, and identified novel independent prognostic markers and models for standard-risk patients with non-WNT/non-SHH disease. Because of the scarcity and low quality of available genomic material, we used a mass spectrometry-minimal methylation classifier assay (MS-MIMIC) to assess methylation subgroup and a molecular inversion probe array to detect genome-wide copy number aberrations. Prognostic biomarkers and models identified were validated in an independent, demographically matched cohort (n=70) of medulloblastoma patients with non-WNT/non-SHH standard-risk disease treated with conventional therapies (maximal surgical resection followed by adjuvant craniospinal irradiation [all patients] and chemotherapy [65 of 70 patients], at UK Children's Cancer and Leukaemia Group and European Society for Paediatric Oncology (SIOPE) associated treatment centres between 1990 and 2014. These samples were analysed by Illumina 450k DNA methylation microarray. HIT-SIOP PNET 4 is registered with ClinicalTrials.gov, number NCT01351870.FindingsWe analysed methylation subgroup, genome-wide copy number aberrations, and mutational features in 136 assessable tumour samples from the HIT-SIOP PNET 4 cohort, representing 40% of the 338 patients in the trial cohort. This cohort of 136 samples consisted of 28 (21%) classified as WNT, 17 (13%) as SHH, and 91 (67%) as non-WNT/non-SHH (we considered Group3 and Group4 medulloblastoma together in our analysis because of their similar molecular and clinical features). Favourable outcomes for WNT tumours were confirmed in patients younger than 16 years, and all relapse events in SHH (four [24%] of 17) occurred in patients with TP53 mutation (TP53mut) or chromosome 17p loss. A novel whole chromosomal aberration signature associated with increased ploidy and multiple non-random whole chromosomal aberrations was identified in 38 (42%) of the 91 samples from patients with non-WNT/non-SHH medulloblastoma in the HIT-SIOP PNET 4 cohort. Biomarkers associated with this whole chromosomal aberration signature (at least two of chromosome 7 gain, chromosome 8 loss, and chromosome 11 loss) predicted favourable prognosis. Patients with non-WNT/non-SHH medulloblastoma could be reclassified by these markers as having favourable-risk or high-risk disease. In patients in the HIT-SIOP PNET4 cohort with non-WNT/non-SHH medulloblastoma, with a median follow-up of 6·7 years (IQR 5·8–8·2), 5-year event-free survival was 100% in the favourable-risk group and 68% (95% CI 57·5–82·7; p=0·00014) in the high-risk group. In the validation cohort, with a median follow-up of 5·6 years (IQR 3·1–8·1), 5-year event-free survival was 94·7% (95% CI 85·2–100) in the favourable-risk group and 58·6% (95% CI 45·1–76·1) in the high-risk group (hazard ratio 9·41, 95% CI 1·25–70·57; p=0·029). Our comprehensive molecular investigation identified subgroup-specific risk models which allowed 69 (51%) of 134 accessible patients from the standard-risk medulloblastoma HIT-SIOP PNET 4 cohort to be assigned to a favourable-risk group.InterpretationWe define a whole chromosomal signature that allows the assignment of non-WNT/non-SHH medulloblastoma patients normally classified as standard-risk into favourable-risk and high-risk categories. In addition to patients younger than 16 years with WNT tumours, patients with non-WNT/non-SHH tumours with our defined whole chromosomal aberration signature and patients with SHH-TP53wild-type tumours should be considered for therapy de-escalation in future biomarker-driven, risk-adapted clinical trials. The remaining subgroups of patients with high-risk medulloblastoma might benefit from more intensive therapies.FundingCancer Research UK, Swedish Childhood Cancer Foundation, French Ministry of Health/French National Cancer Institute, and the German Children's Cancer Foundation.

Diagnostic moléculaire des gliomes diffus

Diffuse gliomas are the most common primitive tumors of the central nervous system (CNS). Those are infîltrative neoplasms with a dismal prognosis and a tendency to malignant transformation. The 2016 WHO classification of CNS tumors distin-guishes diffuse astrocytomas from oligodendrogliomas. Diffuse gliomas are classified according to the status of IDH1/2 genes since IDH1/2 mutations are associated with a better prognosis. Among the IDH-mutant gliomas, oligodendrogliomas display a combined loss of chromosomal arms 1p and 19q (1p/19q codeletion) whereas diffuse astrocytomas harbor mutation of ATRX and TP53 genes. The 1 p/19q codeletion is associated with a longer survival (> 15 years). Among the IDH-wild type diffuse gliomas, glioblastomas (GB) represent the most frequent and most aggressive form, with a median survival of 15 months. GB display EGFR gene amplification, chromosome 7 gain and chromosome 10 loss. Diffuse midline gliomas (brainstem), most common in children, habor a K27M mutation of histone genes H3F3/HIST1H3B, associated with a very short survival (< 1 year). The G34R/V mutation of H3F3 gene is present in diffuse gliomas of the cerebral hemispheres in adolescents. Such a histomolecular classification of diffuse gliomas is more objective than histology alone and will be the basis of personalized medicine in the years to come.