Adult pilocytic astrocytoma in the molecular era: a comprehensive review

Adult pilocytic astrocytoma (PA) is less prevalent than pediatric PA and is associated with a worse prognosis. In a literature review, we found that 88.3% of the molecular alterations in adult PA are associated with MAPK pathway dysregulation. The most common alterations are fusions of BRAF. Understanding of the mechanisms underlying this pathway has evolved substantially, heralding advancements in specific targeted therapy. Here, we review clinical and molecular features of adult PA, characteristics predicting aggressive behavior and approaches to standard and investigational therapies. We highlight epigenetic profiling and integrated diagnosis as an essential component of classifying PA.

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Molecular correlates of PD-L1 expression in patients (pts) with gastroesophageal (GE) cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.4558 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 4558-4558

Author(s):

Jingyuan Wang ◽

Joanne Xiu ◽

Anthony Frank Shields ◽

Axel Grothey ◽

Benjamin Adam Weinberg ◽

...

Keyword(s):

Mapk Pathway ◽

Epigenetic Modification ◽

Gene Mutations ◽

Mutation Rates ◽

Missense Mutations ◽

Chi Square ◽

Expression Levels ◽

Molecular Alterations ◽

Molecular Features ◽

The Impact

4558 Background: The increased PD-L1 expression evaluated by combined positive score (CPS) is associated with improved efficacy of immunotherapy in GE cancers. The impact of tumor molecular alterations on PD-L1 expression is still not well-studied. We aimed to characterize specific molecular features of tumors with different CPS levels in GE cancers. Methods: 2,707 GE tumors [1,662 gastric/GE junction adenocarcinoma (GA), 856 esophageal adenocarcinoma (EA), 75 esophageal squamous (ES) and 114 GE unspecified] collected between 2000.8 and 2019.7 were analyzed using NextGen DNA sequencing (NGS), immunohistochemistry (IHC) and fragment analysis (FA) (Caris Life Sciences, Phoenix, AZ). Tumor mutation burden (TMB) was calculated based on somatic nonsynonymous missense mutations. dMMR/MSI status was evaluated by a combination of IHC, FA and NGS. PD-L1 expression measured by IHC (22c3) was evaluated by CPS scores. Molecular alterations were compared in three groups (CPS ≥ 10, H; CPS = 1~9, M; CPS = 0, L) using Fisher-Exact or Chi-square and adjusted for multiple comparison by Benjamini-Hochberg. Significance was determined by adjusted (adj) p < .05. Results: Overall, CPS-H, M, and L were seen in 18% (n = 494), 28% (n = 765) and 53% (n = 1,448) of GE tumors respectively. CPS-H was the most prevalent in ES (43%) followed by GA (19%) and lowest in EA (14%). Overall, TMB was similar between CPS-L and M, but was significantly increased in H (average TMB = 8.4 vs. 8.6 vs. 11 mt/MB, adj p < .0001); the effect was seen in EA and GA, but not in ES. An overall significant association between MSI/dMMR status and PD-L1 expression levels was seen (2%, 3.2% and 12% in CPS-L, M and H, adj p < .05) in GE tumors; the significance was seen in GA, but not in EA or ES. Amplifications of PD-L1 (H: 1.5%, M: 0.1% and L: 0) and PD-L2 (H: 1.1%, M: 0.1%, L: 0) were the highest in CPS-H, while ASPSCR1 (H: 0, M: 0, L: 1%) and TNFRSF14 (H: 0, M: 0.4, L: 2%) were the lowest (adj p < .01). Genes involved in epigenetic modification (top 5: ARID1A, ASXL1, BCL9, BCOR, CREBBP), MAPK ( KRAS, MAP2K1) and mismatch repair ( MLH1, MSH6) had the highest mutation rates in CPS-H, compared to M and L ( p < .0001). In contrast, CDH1 had higher mutation rates in CPS-L (12%), compared to M and H (5% and 5%) ( p < .0001). Conclusions: This is the largest study to investigate the distinct molecular landscape of pts with different PD-L1 expression levels in GE cancers. Our data may provide novel insights for pt selection (e.g. pts with gene mutations involved in epigenetic modification) and the development of rational combination immunotherapy (e.g. drugs targeting MAPK pathway).

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Molecular Alterations Of Low-Grade Gliomas In Young Patients: Strategies And Platforms For Routine Evaluation

Neuro-Oncology Practice ◽

10.1093/nop/npab053 ◽

2021 ◽

Author(s):

Iman Dandapath ◽

Rituparna Chakraborty ◽

Kavneet Kaur ◽

Swati Mahajan ◽

Jyotsna Singh ◽

...

Keyword(s):

Mapk Pathway ◽

Young Patients ◽

Steering Committee ◽

Mitogen Activated Protein Kinase ◽

Low Grade ◽

Low Grade Gliomas ◽

Molecular Alterations ◽

Integrated Diagnosis ◽

Mitogen Activated Protein ◽

Diffuse Gliomas

Abstract In recent years, it has been established that molecular biology of pediatric low-grade gliomas (PLGGs) is entirely distinct from adults. The majority of the circumscribed pediatric gliomas are driven by mitogen-activated protein kinase (MAPK) pathway, which has yielded important diagnostic, prognostic, and therapeutic biomarkers. Further, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT) Steering Committee in their fourth meeting, suggested including a panel of molecular markers for integrated diagnosis in "pediatric type" diffuse gliomas. However, a designated set of platforms for the evaluation of these alterations has yet not been mentioned for easier implementation in routine molecular diagnostics. Herein, we have reviewed the relevance of analyzing these markers and discussed the strategies and platforms best apposite for clinical laboratories.

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Diffuse Large B-Cell Lymphoma: Recognition of Markers for Targeted Therapy

Hemato ◽

10.3390/hemato2020017 ◽

2021 ◽

Vol 2 (2) ◽

pp. 281-304

Author(s):

Laura Tomas-Roca ◽

Marta Rodriguez ◽

Ruth Alonso-Alonso ◽

Socorro M. Rodriguez-Pinilla ◽

Miguel Angel Piris

Keyword(s):

Targeted Therapy ◽

B Cells ◽

B Cell ◽

B Cell Lymphoma ◽

Therapeutic Approaches ◽

Molecular Features ◽

Molecular Variants ◽

The Status ◽

Underlying Causes ◽

Large B Cell

Diffuse large B-cell lymphomas (DLBCL)s, the most common type of Non-Hodgkin’s Lymphoma, constitute a heterogeneous group of disorders including different disease sites, strikingly diverse molecular features and a profound variability in the clinical behavior. Molecular studies and clinical trials have partially revealed the underlying causes for this variability and have made possible the recognition of some molecular variants susceptible of specific therapeutic approaches. The main histogenetic groups include the germinal center, activated B cells, thymic B cells and terminally differentiated B cells, a basic scheme where the large majority of DLBCL cases can be ascribed. The nodal/extranodal origin, specific mutational changes and microenvironment peculiarities provide additional layers of complexity. Here, we summarize the status of the knowledge and make some specific proposals for addressing the future development of targeted therapy for DLBC cases.

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LGG-23. EXCELLENT CLINICAL / RADIOLOGICAL RESPONSE TO BRAF INHIBITION IN A YOUNG CHILD WITH IN-OPERABLE SUPRA-SELLAR PILOCYTIC ASTROCYTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.405 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii370-iii371

Author(s):

Stacy Chapman ◽

Demitre Serletis ◽

Colin Kazina ◽

Mubeen Rafay ◽

Sherry Krawitz ◽

...

Keyword(s):

Targeted Therapy ◽

Pilocytic Astrocytoma ◽

Clinical Symptoms ◽

Obstructive Hydrocephalus ◽

Braf V600e Mutation ◽

Braf V600e ◽

Low Grade ◽

Dramatic Improvement ◽

Chemotherapeutic Regimen ◽

Response To Chemotherapy

Abstract In-operable low grade gliomas (LGG) in the pediatric population continue to present a treatment dilemma. Due to the low-grade nature of these tumors, and variable response to chemotherapy / radiation, the choice of adjuvant treatment is difficult. Overall survival is directly related to the degree of surgical resection, adding complexity to these inoperable tumors. Current chemotherapeutic regimen for these inoperable tumors includes vincristine (VCR) and carboplatin (Carbo). With advancements in the molecular characterization of gliomas, the role of targeted therapy has come into question. We present a 2-year-old female with biopsy proven Pilocytic Astrocytoma (positive BRAF-V600E mutation) involving the hypothalamic/optic chiasm region. She presented with ataxic gait, bi-temporal hemianopia, obstructive hydrocephalus and central hypothyroidism, which progressed to altered consciousness, and right hemiparesis due to location/mass effect of the tumor. She was initially treated with chemotherapy (VCR/Carbo) but her tumor progressed at 6 weeks of treatment. As her tumor was positive for BRAF-V600E mutation, she was started on Dabrafenib monotherapy, resulting in dramatic improvement in her clinical symptoms (able to stand, improved vision), and a 60% reduction in tumor size at 3-months. At 6-months, follow up MRI showed slight increase in the solid portion of the tumor, with no clinical symptoms. We plan to add MEK inhibitor (Trametinib) and continue with Dabrafenib. Our experience and literature review suggests that LGG with BRAF-V600E mutations may benefit from upfront targeted therapy. Prospective clinical trials comparing the efficacy of BRAF inhibitors versus standard chemotherapy in LGG with BRAF mutations are urgently needed.

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Hypoplastic Myelodysplastic Syndromes: Just an Overlap Syndrome?

Cancers ◽

10.3390/cancers13010132 ◽

2021 ◽

Vol 13 (1) ◽

pp. 132

Author(s):

Bruno Fattizzo ◽

Fabio Serpenti ◽

Wilma Barcellini ◽

Chiara Caprioli

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Clonal Selection ◽

Cytotoxic T Cells ◽

Immunosuppressive Treatment ◽

Young Patients ◽

Suppressor Cells ◽

Molecular Alterations ◽

Molecular Features ◽

Increased Risk

Myelodysplasias with hypocellular bone marrow (hMDS) represent about 10–15% of MDS and are defined by reduced bone marrow cellularity (i.e., <25% or an inappropriately reduced cellularity for their age in young patients). Their diagnosis is still an object of debate and has not been clearly established in the recent WHO classification. Clinical and morphological overlaps with both normo/hypercellular MDS and aplastic anemia include cytopenias, the presence of marrow hypocellularity and dysplasia, and cytogenetic and molecular alterations. Activation of the immune system against the hematopoietic precursors, typical of aplastic anemia, is reckoned even in hMDS and may account for the response to immunosuppressive treatment. Finally, the hMDS outcome seems more favorable than that of normo/hypercellular MDS patients. In this review, we analyze the available literature on hMDS, focusing on clinical, immunological, and molecular features. We show that hMDS pathogenesis and clinical presentation are peculiar, albeit in-between aplastic anemia (AA) and normo/hypercellular MDS. Two different hMDS phenotypes may be encountered: one featured by inflammation and immune activation, with increased cytotoxic T cells, increased T and B regulatory cells, and better response to immunosuppression; and the other, resembling MDS, where T and B regulatory/suppressor cells prevail, leading to genetic clonal selection and an increased risk of leukemic evolution. The identification of the prevailing hMDS phenotype might assist treatment choice, inform prognosis, and suggest personalized monitoring.

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Oncogenic FAM131B–BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma

Acta Neuropathologica ◽

10.1007/s00401-011-0817-z ◽

2011 ◽

Vol 121 (6) ◽

pp. 763-774 ◽

Cited By ~ 154

Author(s):

Huriye Cin ◽

Claus Meyer ◽

Ricarda Herr ◽

Wibke G. Janzarik ◽

Sally Lambert ◽

...

Keyword(s):

Pilocytic Astrocytoma ◽

Mapk Pathway ◽

Alternative Mechanism ◽

Pathway Activation ◽

Braf Fusion

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Molecular determinants of therapy response of venetoclax-based combinations in acute myeloid leukemia

Biological Chemistry ◽

10.1515/hsz-2021-0288 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Philipp Makowka ◽

Verena Stolp ◽

Karoline Stoschek ◽

Hubert Serve

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Current Knowledge ◽

Therapy Response ◽

Secondary Resistance ◽

Molecular Alterations ◽

Molecular Features ◽

Slow Progress ◽

Molecular Aberrations ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous, highly malignant disease of the bone marrow. After decades of slow progress, recent years saw a surge of novel agents for its treatment. The most recent advancement is the registration of the Bcl-2 inhibitor ventoclax in combination with a hypomethylating agent (HMA) in the US and Europe for AML patients not eligible for intensive chemotherapy. Treatment of newly diagnosed AML patients with this combination results in remission rates that so far could only be achieved with intensive treatment. However, not all AML patients respond equally well, and some patients relapse early, while other patients experience longer periods of complete remission. A hallmark of AML is its remarkable genetic, molecular and clinical heterogeneity. Here, we review the current knowledge about molecular features of AML that help estimate the probability of response to venetoclax-containing therapies. In contrast to other newly developed AML therapies that target specific recurrent molecular alterations, it seems so far that responses are not specific for a certain subgroup. One exception is spliceosome mutations, where good response has been observed in clinical trials with venetoclax/azacitidine. These mutations are rather associated with a more unfavorable outcome with chemotherapy. In summary, venetoclax in combination with hypomethylating agents represents a significant novel option for AML patients with various molecular aberrations. Mechanisms of primary and secondary resistance seem to overlap with those towards chemotherapy.

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Molecular characterization of the Ras-MAPK pathway in metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1034 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1034-1034

Author(s):

Justin Wayne Wong Tiu-lim ◽

Jun Yin ◽

Joanne Xiu ◽

Wolfgang Michael Korn ◽

Heinz-Josef Lenz ◽

...

Keyword(s):

Breast Cancer ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Mapk Pathway ◽

Metastatic Breast ◽

Molecular Alterations ◽

Ras Genes ◽

Mutational Status ◽

Pathway Activation ◽

Class 1

1034 Background: The Ras-MAPK pathway is a known driver of tumorigenesis and therapeutic target in a variety of cancers. Alterations in this pathway have been linked to decreased tumor immunogenicity. However, molecular alterations in the Ras-MAPK are rare in breast cancer (BC) and their clinical implications remain unclear. As mutational status does not accurately correlate with transcriptional activity, a MAPK pathway activity score (MPAS, Wagle et al., 2018, npj Precision Medicine) is indicative of MAPK activation and correlates with response to MEK (MEKi) or BRAF inhibition (BRAFi). Our goal was to determine the frequency of molecular alterations in the Ras-MAPK and correlate to MAPK pathway activation in MBC. Methods: A total of 6464 BC samples underwent comprehensive molecular profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq; whole exome sequencing, NovaSEQ), RNA (NovaSeq, whole transcriptome sequencing, WTS) and IHC. MPAS and immune cell fraction (ICF, Quantiseq) were assessed by mRNA analysis. Wilcoxon, Fisher’s exact, or Dunnett’s test was used. All results shown were statistically significant (p < 0.05). Results: The predominant alteration of RAS genes was mutation followed by amplification, no fusions were detected (Table). Only 0.17% of all tumors harbor KRAS G12c mutations. The highest MPAS scores were found in KRAS mutants (mut), HRAS mut (Q61, G1213), BRAF V600 (class 1) mut and NRAS Q61 mut (Table) and therefore used to define Genomic MAPK Activated Tumors (GMAT). GMAT compared to wild type (WT) had significantly higher PD-L1 expression, TMB and MSI/dMMR. GMAT had less B cells (3.4% vs 4.4%), more M1 Macrophages (4.4% vs 3.4%) and neutrophils (5.5% vs 2.7%) regardless of HR status but less NK cells (2.3% s 3.0%), MSDCs (0.9% vs 3.0%) only in HR- tumors with respect to WT. GMAT tumors showed more frequent mutation rate (mr) of PIK3CA (HR+: 57.3% vs 40%; HR-: 41.9% vs 17.9%). HR+ tumors had a higher mr of MSH3 (11.8% vs 0.6%) while HR- tumors had higher mr of PIK3R1 (9.6% vs 3.8%), RhoA (5.3% vs 0.5%), DNA repair genes (TERT, 18.2% vs 1.0%; ARID1A, 18.2% vs 5.9%; PRKDC, 3.9% vs 0) and lower TP53 mr (54.5% vs 85.8%) compared to WT. Conclusions: Our study demonstrates that RAS, BRAF and MEK1 mutations are associated with MAPK pathway activation indicative of benefit from MEKi or BRAFi. GMAT warrant further investigation for combinations targeting the RAS-MAPK pathway and immune checkpoint inhibitors.[Table: see text]

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