Vito Alessandro Lasorsa

Bio: Vito Alessandro Lasorsa is an academic researcher from University of Naples Federico II. The author has contributed to research in topics: Medicine & Neuroblastoma. The author has an hindex of 9, co-authored 27 publications receiving 293 citations.

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression.

Abstract: // Vito Alessandro Lasorsa 1,2 , Daniela Formicola 1,2 , Piero Pignataro 1,2 , Flora Cimmino 1,2 , Francesco Maria Calabrese 3 , Jaume Mora 4 , Maria Rosaria Esposito 5 , Marcella Pantile 5 , Carlo Zanon 5 , Marilena De Mariano 6 , Luca Longo 6 , Michael D. Hogarty 7 , Carmen de Torres 4 , Gian Paolo Tonini 5 , Achille Iolascon 1,2 and Mario Capasso 1,2,8 1 University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy 2 CEINGE Biotecnolgie Avanzate, Naples, Italy 3 University of Bari, Department of Biology, Bari, Italy 4 Hospital Sant Joan de Deu, Developmental Tumor Biology Laboratory and Department of Oncology, Esplugues de Llobregat, Barcelona, Spain 5 Pediatric Research Institute (IRP), Fondazione Citta della Speranza, Neuroblastoma Laboratory, Padua, Italy 6 U.O.C. Bioterapie, IRCCS AOU San Martino-IST, National Cancer Research Institute, Genoa, Italy 7 Children’s Hospital of Philadelphia, Division of Oncology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America 8 IRCCS SDN, Istituto di Ricerca Diagnostica e Nucleare, Naples, Italy Correspondence: Mario Capasso, email: // Flora Cimmino, email: // Keywords : NGS, neuroblastoma, high risk, somatic mutation, cancer driver genes Received : December 22, 2015 Accepted : February 09, 2016 Published : March 18, 2016 Abstract The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma. Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines. We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9 , a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK . Other genes ( PTK2 , NAV3 , NAV1 , FZD1 and ATRX ), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%. Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression. Notably BARD1 , CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants. In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression.

HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia

Abstract: HIF1A (Hypoxia-Inducible-Factor 1A) expression in solid tumors is relevant to establish resistance to therapeutic approaches. The use of compounds direct against hypoxia signaling and HIF1A does not show clinical efficiency because of changeable oxygen concentrations in solid tumor areas. The identification of HIF1A targets expressed in both normoxia and hypoxia and of HIF1A/hypoxia signatures might meliorate the prognostic stratification and therapeutic successes in patients with high-risk solid tumors. In this study, we conducted a combined analysis of RNA expression and DNA methylation of neuroblastoma cells silenced or unsilenced for HIF1A expression, grown in normoxia and hypoxia conditions. The analysis of pathways highlights HIF-1 (heterodimeric transcription factor 1) activity in normoxia in metabolic process and HIF-1 activity in hypoxia in neuronal differentiation process. HIF1A driven transcriptional response in hypoxia depends on epigenetic control at DNA methylation status of gene regulatory regions. Furthermore, low oxygen levels generate HIF1A-dependent or HIF1A-independent signatures, able to stratify patients according to risk categories. These findings may help to understand the molecular mechanisms by which low oxygen levels reshape gene signatures and provide new direction for hypoxia targeting in solid tumor.

An 18 gene expression‑based score classifier predicts the clinical outcome in stage 4 neuroblastoma

Abstract: The prognosis of children with metastatic stage 4 neuroblastoma (NB) has remained poor in the past decade. Using microarray analyses of 342 primary tumors, we here developed and validated an easy to use gene expression-based risk score including 18 genes, which can robustly predict the outcome of stage 4 patients. This classifier was a significant predictor of overall survival in two independent validation cohorts [cohort 1 (n = 214): P = 6.3 × 10−5; cohort 2 (n = 27): P = 3.1 × 10−2]. The prognostic value of the risk score was validated by multivariate analysis including the established markers age and MYCN status (P = 0.027). In the pooled validation cohorts (n = 241), integration of the risk score with the age and/or MYCN status identified subgroups with significantly differing overall survival (ranging from 35 to 100 %). Together, the 18-gene risk score classifier can identify patients with stage 4 NB with favorable outcome and may therefore improve risk assessment and treatment stratification of NB patients with disseminated disease.

An 18 gene expression-based score classifier predicts the clinical outcome in stage 4

Abstract: Background: The prognosis of children with metastatic stage 4 neuroblastoma (NB) has remained poor in the past decade. Patients and methods: Using microarray analyses of 342 primary tumors, we here developed and validated an easy to use gene expression-based risk score including 18 genes, which can robustly predict the outcome of stage 4 patients. Results: This classifier was a significant predictor of overall survival in two independent validation cohorts [cohort 1 (n = 214): P = 6.3 × 10 −5 ; cohort 2 (n = 27): P = 3.1 × 10 −2 ]. The prognostic value of the risk score was validated by multivariate analysis including the established markers age and MYCN status (P = 0.027). In the pooled validation cohorts (n = 241), integration of the risk score with the age and/or MYCN status identified subgroups with significantly differing overall survival (ranging from 35 to 100 %). Conclusion: Together, the 18-gene risk score classifier can identify patients with stage 4 NB with favorable outcome and may therefore improve risk assessment and treatment stratification of NB patients with disseminated disease.

Patterns of Somatic Mutation in Human Cancer Genomes

Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore PL02-05 All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Integrative Genomics Viewer

Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

MicroRNAs: Target Recognition and Regulatory Functions

Abstract: MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

Neuroblastoma

Abstract: Neuroblastoma is a type of cancer that most often affects children. Neuroblastoma occurs when immature nerve cells called neuroblasts become abnormal and multiply uncontrollably to form a tumor. Most commonly, the tumor originates in the nerve tissue of the adrenal gland located above each kidney. Other common sites for tumors to form include the nerve tissue in the abdomen, chest, neck, or pelvis. Neuroblastoma can spread (metastasize) to other parts of the body such as the bones, liver, or skin.

Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells.

Abstract: How severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remains largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected Huh7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a dose-dependent activation of Akt, mTOR, S6K1 and 4E-BP1 at 24 hours post infection (hpi). However, we found a significant inhibition of HIF-1α through 24hpi and 48hpi of the infection, suggesting a crosstalk between the SARS-CoV-2 and the Akt/mTOR/HIF-1 signaling pathways. Inhibition of the mTOR signaling pathway using Akt inhibitor MK-2206 showed a significant reduction in virus production. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe coronavirus disease 2019 (COVID-19) patients.