Project description:Inverted sinonasal papilloma (ISP) is a locally aggressive neoplasm associated with sinonasal squamous cell carcinoma (SNSCC) in 10% to 25% of cases. To date, no recurrent mutations have been identified in ISP or SNSCC. Using targeted next-generation sequencing and Sanger sequencing, we identified activating EGFR mutations in 88% of ISP and 77% of ISP-associated SNSCC. Identical EGFR genotypes were found in matched pairs of ISP and associated SNSCC, providing the first genetic evidence of a biologic link between these tumors. EGFR mutations were not identified in exophytic or oncocytic papillomas or non-ISP-associated SNSCC, suggesting that the ISP/SNSCC spectrum is biologically distinct among sinonasal squamous tumors. Patients with ISP harboring EGFR mutations also exhibited an increased progression-free survival compared with those with wild-type EGFR. Finally, treatment of ISP-associated carcinoma cells with irreversible EGFR inhibitors resulted in inactivation of EGFR signaling and growth inhibition. These findings implicate a prominent role for activating EGFR mutations in the pathogenesis of ISP and associated SNSCC and rationalize consideration of irreversible EGFR inhibitors in the therapy of these tumors.
Project description:Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.
Project description:Extra-nodal NK/T-cell lymphoma, nasal type (ENKTCL) is a highly aggressive Epstein-Barr virus associated lymphoma, typically presenting in the nasal and paranasal areas. We assembled a large series of ENKTCL (n = 209) for comprehensive genomic analysis and correlative clinical study. The International Lymphoma Prognostic Index (IPI), site of disease, stage, lymphadenopathy, and hepatomegaly were associated with overall survival. Genetic analysis revealed frequent oncogenic activation of the JAK/STAT3 pathway and alterations in tumor suppressor genes (TSGs) and genes associated with epigenomic regulation. Integrated genomic analysis including recurrent mutations and genomic copy number alterations using consensus clustering identified seven distinct genetic clusters that were associated with different clinical outcomes, thus constituting previously unrecognized risk groups. The genetic profiles of ENTKCLs from Asian and Hispanic ethnic groups showed striking similarity, indicating shared pathogenetic mechanism and tumor evolution. Interestingly, we discovered a novel functional cooperation between activating STAT3 mutations and loss of the TSG, PRDM1, in promoting NK-cell growth and survival. This study provides a genetic roadmap for further analysis and facilitates investigation of actionable therapeutic opportunities in this aggressive lymphoma.
Project description:In diffuse large B cell lymphoma (DLBCL), tumors belonging to the ABC but not GCB gene expression subgroup rely upon chronic active B cell receptor signaling for viability, a dependency that is targetable by ibrutinib. A phase III trial ("Phoenix;" ClinicalTrials.gov: NCT01855750) showed a survival benefit of ibrutinib addition to R-CHOP chemotherapy in younger patients with non-GCB DLBCL, but the molecular basis for this benefit was unclear. Analysis of biopsies from Phoenix trial patients revealed three previously characterized genetic subtypes of DLBCL: MCD, BN2, and N1. The 3-year event-free survival of younger patients (age ≤60 years) treated with ibrutinib plus R-CHOP was 100% in the MCD and N1 subtypes while the survival of patients with these subtypes treated with R-CHOP alone was significantly inferior (42.9% and 50%, respectively). This work provides a mechanistic understanding of the benefit of ibrutinib addition to chemotherapy, supporting its use in younger patients with non-GCB DLBCL.
Project description:BACKGROUND:Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. METHODS AND FINDINGS:To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in beta-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas. CONCLUSIONS:The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life.
Project description:Fragile X syndrome (FXS) is characterized by variable neurobehavioral abnormalities, which leads to difficulties in developing and evaluating treatments and in determining accurate prognosis. We employed a pediatric cross-sectional sample (1,072 males, 338 females) from FORWARD, a clinic-based natural history study, to identify behavioral subtypes by latent class analysis. Input included co-occurring behavioral conditions, sleep and sensory problems, autistic behavior scales (SCQ, SRS-2), and the Aberrant Behavior Checklist revised for FXS (ABCFX). A 5-class solution yielded the most clinically meaningful, pharmacotherapy independent behavioral groups with distinctive SCQ, SRS-2, and ABCFX profiles, and adequate non-overlap (≥ 71%): "Mild" (31%), "Moderate without Social Impairment" (32%), "Moderate with Social Impairment" (7%), "Moderate with Disruptive Behavior" (20%), and "Severe" (9%). Our findings support FXS subtyping, for improving clinical management and therapeutic development.
Project description:UnlabelledKaposi's sarcoma (KS), caused by KS-associated herpesvirus (KSHV), is the most common cancer among HIV-infected patients in Malawi and in the United States today. In Malawi, KSHV is endemic. We conducted a cross-sectional study of patients with HIV infection and KS with no history of chemo- or antiretroviral therapy (ART). Seventy patients were enrolled. Eighty-one percent had T1 (advanced) KS. Median CD4 and HIV RNA levels were 181 cells/mm(3) and 138,641 copies/ml, respectively. We had complete information and suitable plasma and biopsy samples for 66 patients. For 59/66 (89%) patients, a detectable KSHV load was found in plasma (median, 2,291 copies/ml; interquartile range [IQR], 741 to 5,623). We utilized a novel KSHV real-time quantitative PCR (qPCR) array with multiple primers per open reading frame to examine KSHV transcription. Seventeen samples exhibited only minimal levels of KSHV mRNAs, presumably due to the limited number of infected cells. For all other biopsy samples, the viral latency locus (LANA, vCyc, vFLIP, kaposin, and microRNAs [miRNAs]) was transcribed abundantly, as was K15 mRNA. We could identify two subtypes of treatment-naive KS: lesions that transcribed viral RNAs across the length of the viral genome and lesions that displayed only limited transcription restricted to the latency locus. This finding demonstrates for the first time the existence of multiple subtypes of KS lesions in HIV- and KS-treatment naive patients.ImportanceKS is the leading cancer in people infected with HIV worldwide and is causally linked to KSHV infection. Using viral transcription profiling, we have demonstrated the existence of multiple subtypes of KS lesions for the first time in HIV- and KS-treatment-naive patients. A substantial number of lesions transcribe mRNAs which encode the viral kinases and hence could be targeted by the antiviral drugs ganciclovir or AZT in addition to chemotherapy.
Project description:BackgroundParkinson's Disease (PD) varies widely among individuals, and Artificial Intelligence (AI) has recently helped to identify three disease progression subtypes. While their clinical features are already known, their gene expression profiles remain unexplored.ObjectivesThe objectives of this study were (1) to describe the transcriptomics characteristics of three PD progression subtypes identified by AI, and (2) to evaluate if gene expression data can be used to predict disease subtype at baseline.DesignThis is a retrospective longitudinal cohort study utilizing the Parkinson's Progression Markers Initiative (PPMI) database.MethodsWhole blood RNA-Sequencing data underwent differential gene expression analysis, followed by multiple pathway analyses. A Machine Learning (ML) classifier, namely XGBoost, was trained using data from multiple modalities, including gene expression values.ResultsOur study identified differentially expressed genes (DEGs) that were uniquely associated with Parkinson's disease (PD) progression subtypes. Importantly, these DEGs had not been previously linked to PD. Gene-pathway analysis revealed both distinct and shared characteristics between the subtypes. Notably, two subtypes displayed opposite expression patterns for pathways involved in immune response alterations. In contrast, the third subtype exhibited a more unique profile characterized by increased expression of genes related to detoxification processes. All three subtypes showed a significant modulation of pathways related to the regulation of gene expression, metabolism, and cell signaling. ML revealed that the progression subtype with the worst prognosis can be predicted at baseline with 0.877 AUROC, yet the contribution of gene expression was marginal for the prediction of the subtypes.ConclusionThis study provides novel information regarding the transcriptomics profiles of PD progression subtypes, which may foster precision medicine with relevant indications for a finer-grained diagnosis and prognosis.
Project description:PurposePatients with SCLC rarely undergo biopsies at relapse. When pursued, tissue obtained can be inadequate for molecular testing, posing a challenge in identifying potentially targetable alterations in a clinically meaningful time frame. We examined the feasibility of circulating tumor DNA (ctDNA) testing in identifying potentially targetable alterations in SCLC.Experimental designctDNA test results were prospectively collected from patients with SCLC between 2014 and 2017 and analyzed. ctDNA profiles of SCLC at diagnosis and relapse were also compared.ResultsA total of 609 samples collected from 564 patients between 2014 and 2017 were analyzed. The median turnaround time for test results was 14 days. Among patients with data on treatment status, there were 61 samples from 59 patients and 219 samples from 206 patients collected at diagnosis and relapse, respectively. The number of mutations or amplifications detected per sample did not differ by treatment status. Potentially targetable alterations in DNA repair, MAPK and PI3K pathways, and genes such as MYC and ARID1A were identifiable through ctDNA testing. Furthermore, our results support that it may be possible to reconstruct the clonal relationship between detected variants through ctDNA testing.ConclusionsPatients with relapsed SCLC rarely undergo biopsies for molecular testing and often require prompt treatment initiation. ctDNA testing is less invasive and capable of identifying alterations in relapsed disease in a clinically meaningful timeframe. ctDNA testing on an expanded gene panel has the potential to advance our knowledge of the mechanisms underlying treatment resistance in SCLC and aid in the development of novel treatment strategies.
Project description:Tumor protein 53 mutation (TP53mut) is one of the most important driver events facilitating tumorigenesis, which could induce a series of chain reactions to promote tumor malignant transformation. However, the malignancy progression patterns under TP53 mutation remain less known. Clarifying the molecular landscapes of TP53mut tumors will help us understand the process of tumor development and aid precise treatment. Here, we distilled genetic and epigenetic features altered in TP53mut cancers for cluster-of-clusters analysis. Using integrated classification, we derived 5 different subtypes of TP53mut patients. These subtypes have distinct features in genomic alteration, clinical relevance, microenvironment dysregulation, and potential therapeutics. Among the 5 subtypes, COCA3 was identified as the subtype with worst prognosis, causing an immunosuppressive microenvironment and immunotherapeutic resistance. Further drug efficacy research highlighted olaparib as the most promising therapeutic agents for COCA3 tumors. Importantly, the therapeutic efficacy of olaparib in COCA3 and immunotherapy in non-COCA3 tumors was validated via in vivo experimentation. Our study explored the important molecular events and developed a subtype classification system with distinct targeted therapy strategies for different subtypes of TP53mut tumors. These multiomics classification systems provide a valuable resource that significantly expands the knowledge of TP53mut tumors and may eventually benefit in clinical practice.