Tumor Sequencing: Enabling Personalized Targeted Treatments with Informatics

Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

npj Genomic Medicine ◽

10.1038/s41525-020-00163-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Muhammad Aslam ◽

Nirosiya Kandasamy ◽

Anwar Ullah ◽

Nagarajan Paramasivam ◽

Mehmet Ali Öztürk ◽

...

Keyword(s):

Risk Factors ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genetic Variants ◽

Rare Variants ◽

Alpha Synuclein ◽

Younger Age ◽

Targeted Treatments ◽

Genes Encoding ◽

Rare Genetic Variants

AbstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

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Multi-Gene Testing Overview with a Clinical Perspective in Metastatic Triple-Negative Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22137154 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7154

Author(s):

Martina Dameri ◽

Lorenzo Ferrando ◽

Gabriella Cirmena ◽

Claudio Vernieri ◽

Giancarlo Pruneri ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Gene Testing ◽

Repair Deficiency ◽

Targeted Treatments ◽

Recombination Repair ◽

Tumor Mutational Burden ◽

Next Generation Sequencing Ngs

Next-generation sequencing (NGS) is the technology of choice for the routine screening of tumor samples in clinical practice. In this setting, the targeted sequencing of a restricted number of clinically relevant genes represents the most practical option when looking for genetic variants associated with cancer, as well as for the choice of targeted treatments. In this review, we analyze available NGS platforms and clinical applications of multi-gene testing in breast cancer, with a focus on metastatic triple-negative breast cancer (mTNBC). We make an overview of the clinical utility of multi-gene testing in mTNBC, and then, as immunotherapy is emerging as a possible targeted therapy for mTNBC, we also briefly report on the results of the latest clinical trials involving immune checkpoint inhibitors (ICIs) and TNBC, where NGS could play a role for the potential predictive utility of homologous recombination repair deficiency (HRD) and tumor mutational burden (TMB).

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Toward a Personalized Therapy in Soft-Tissue Sarcomas: State of the Art and Future Directions

Cancers ◽

10.3390/cancers13102359 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2359

Author(s):

Liliana Montella ◽

Lucia Altucci ◽

Federica Sarno ◽

Carlo Buonerba ◽

Stefano De Simone ◽

...

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcomas ◽

Chromosomal Translocations ◽

Intrinsic Variability ◽

Poor Survival ◽

Genomic Alterations ◽

Future Directions ◽

Oncogenic Mutations ◽

Targeted Treatments ◽

Innovative Therapies

Soft-tissue sarcomas are rare tumors characterized by pathogenetic, morphological, and clinical intrinsic variability. Median survival of patients with advanced tumors are usually chemo- and radio-resistant, and standard treatments yield low response rates and poor survival results. The identification of defined genomic alterations in sarcoma could represent the premise for targeted treatments. Summarizing, soft-tissue sarcomas can be differentiated into histotypes with reciprocal chromosomal translocations, with defined oncogenic mutations and complex karyotypes. If the latter are improbably approached with targeted treatments, many suggest that innovative therapies interfering with the identified fusion oncoproteins and altered pathways could be potentially resolutive. In most cases, the characteristic genetic signature is discouragingly defined as “undruggable”, which poses a challenge for the development of novel pharmacological approaches. In this review, a summary of genomic alterations recognized in most common soft-tissue sarcoma is reported together with current and future therapeutic opportunities.

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Accucopy: accurate and fast inference of allele-specific copy number alterations from low-coverage low-purity tumor sequencing data

BMC Bioinformatics ◽

10.1186/s12859-020-03924-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Xinping Fan ◽

Guanghao Luo ◽

Yu S. Huang

Keyword(s):

Copy Number ◽

Bayesian Learning ◽

Kernel Smoothing ◽

Gaussian Mixture ◽

Copy Number Alterations ◽

Sequencing Data ◽

Copy Numbers ◽

Allele Specific ◽

Tumor Sequencing ◽

Low Coverage

Abstract Background Copy number alterations (CNAs), due to their large impact on the genome, have been an important contributing factor to oncogenesis and metastasis. Detecting genomic alterations from the shallow-sequencing data of a low-purity tumor sample remains a challenging task. Results We introduce Accucopy, a method to infer total copy numbers (TCNs) and allele-specific copy numbers (ASCNs) from challenging low-purity and low-coverage tumor samples. Accucopy adopts many robust statistical techniques such as kernel smoothing of coverage differentiation information to discern signals from noise and combines ideas from time-series analysis and the signal-processing field to derive a range of estimates for the period in a histogram of coverage differentiation information. Statistical learning models such as the tiered Gaussian mixture model, the expectation–maximization algorithm, and sparse Bayesian learning were customized and built into the model. Accucopy is implemented in C++ /Rust, packaged in a docker image, and supports non-human samples, more at http://www.yfish.org/software/. Conclusions We describe Accucopy, a method that can predict both TCNs and ASCNs from low-coverage low-purity tumor sequencing data. Through comparative analyses in both simulated and real-sequencing samples, we demonstrate that Accucopy is more accurate than Sclust, ABSOLUTE, and Sequenza.

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Genetic and immunologic findings in children with recurrent aphthous stomatitis with systemic inflammation

Pediatric Rheumatology ◽

10.1186/s12969-021-00552-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Martina Girardelli ◽

Erica Valencic ◽

Valentina Moressa ◽

Roberta Margagliotta ◽

Alessandra Tesser ◽

...

Keyword(s):

Clinical Diagnosis ◽

Systemic Inflammation ◽

Lupus Erythematosus ◽

Early Onset ◽

Disease Onset ◽

Recurrent Aphthous Stomatitis ◽

Aphthous Stomatitis ◽

Monogenic Disorders ◽

Pathogenic Variants ◽

Targeted Treatments

Abstract Background Recurrent aphthous stomatitis with systemic signs of inflammation can be encountered in inflammatory bowel disease, Behçet’s disease (BD), Systemic Lupus Erythematosus (SLE). In addition, it has been proposed that cases with very early onset in childhood can be underpinned by rare monogenic defects of immunity, which may require targeted treatments. Thus, subjects with early onset recurrent aphthous stomatitis receiving a clinical diagnosis of BD-like or SLE-like disease may deserve a further diagnostic workout, including immunologic and genetic investigations. Objective To investigate how an immunologic, genetic and transcriptomics assessment of interferon inflammation may improve diagnosis and care in children with recurrent aphthous stomatitis with systemic inflammation. Methods Subjects referred to the pediatric rheumatologist for recurrent aphthous stomatitis associated with signs of systemic inflammation from January 2015 to January 2020 were enrolled in the study and underwent analysis of peripheral lymphocyte subsets, sequencing of a 17-genes panel and measure of interferon score. Results We enrolled 15 subjects (12 females, median age at disease onset 4 years). The clinical diagnosis was BD in 8, incomplete BD in 5, BD/SLE overlap in 1, SLE in 1. Pathogenic genetic variants were detected in 3 patients, respectively 2 STAT1 gain of function variants in two patients classified as BD/SLE overlap and SLE, and 1 TNFAIP3 mutation (A20 haploinsufficiency) in patients with BD. Moreover 2 likely pathogenic variants were identified in DNASE1L3 and PTPN22, both in patients with incomplete BD. Interferon score was high in the two patients with STAT1 GOF mutations, in the patient with TNFAIP3 mutation, and in 3 genetic-negative subjects. In two patients, the treatment was modified based on genetic results. Conclusions Although recurrent aphthous stomatitis associated with systemic inflammation may lead to a clinical diagnosis of BD or SLE, subjects with early disease onset in childhood deserve genetic investigation for rare monogenic disorders. A wider genetic panel may help disclosing the genetic background in the subset of children with increased interferon score, who tested negative in this study.

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EPCO-07. LEVERAGING TRANSCRIPTOME SEQUENCING AND MATHEMATICAL MODELING TO INVESTIGATE GLIOBLASTOMA-MACROPHAGE INTERACTIONS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.286 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii70-ii70

Author(s):

Javier Urcuyo ◽

Andrea Hawkins-Daarud ◽

Susan Massey ◽

Jeffrey Bruce ◽

Peter Canoll ◽

...

Keyword(s):

Immune Cells ◽

Transcriptome Sequencing ◽

Median Overall Survival ◽

Patient Specific ◽

Cell Functions ◽

Targeted Treatments ◽

Spatially Distributed ◽

Suppressive Phenotype ◽

Macrophage Populations ◽

The One

Abstract Glioblastoma (GBM) is the one of the most aggressive and common primary brain malignancies, with a poor median overall survival of less than 15 months. While the immune system is activated and brain-resident microglia and blood-derived macrophages combat the tumor, the tumor can convert some microglia and macrophages to instead exhibit an immune-suppressive phenotype. These co-opted immune cells are thereby termed ‘glioma-associated microglia and macrophages’ (GAMMs), as they allow for continued tumor growth. However, limited clinical data has been collected to understand this phenomenon. As a result, we have collected spatially-distributed image-localized biopsies from a cohort of patients and performed RNA sequencing on each sample. Correlations between normalized RNA counts of genetic markers for macrophages (i.e., CD68, CD163), tumor populations (i.e., SOX2, OLIG2), and key cell functions (i.e., KI67, CASP3) were analyzed. To further investigate the temporal effects that GAMMs have on GBM growth, we proposed the Proliferation-Invasion-Macrophage (PIM) model. This system of partial differential equations incorporates the proliferative and invasive behavior of GBM, as well as populations for both ‘healthy’ and ‘glioma-associated’ macrophages. By exploring the parameter space, we classified the various dynamics of tumor progression and how they relate to the immune response. With further insights of the interactions between GBM and macrophage populations, we can begin to parameterize the model on a patient-specific basis and provide insights to personalized immunotherapies and other novel immune-targeted treatments.

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Long-COVID Syndrome? A Study on the Persistence of Neurological, Psychological and Physiological Symptoms

Healthcare ◽

10.3390/healthcare9050575 ◽

2021 ◽

Vol 9 (5) ◽

pp. 575

Author(s):

Graziella Orrù ◽

Davide Bertelloni ◽

Francesca Diolaiuti ◽

Federico Mucci ◽

Mariagrazia Di Giuseppe ◽

...

Keyword(s):

Quality Of Life ◽

Sleep Disturbances ◽

Online Survey ◽

Clinical Presentation ◽

Demographic Data ◽

Severity Index ◽

Long Term Effects ◽

Targeted Treatments ◽

Euroqol 5D

Background: Emerging aspects of the Covid-19 clinical presentation are its long-term effects, which are characteristic of the so-called “long COVID”. The aim of the present study was to investigate the prevalence of physical, psychological, and sleep disturbances and the quality of life in the general population during the ongoing pandemic. Methods: This study, based on an online survey, collected demographic data, information related to COVID-19, sleep disturbances, and quality of life data from 507 individuals. The level of sleep disturbances and quality of life was assessed through the Insomnia Severity Index (ISI) and the EuroQol-5D (EQ-5D), respectively. Results: In total, 507 individuals (M = 91 and F = 416 women) completed the online survey. The main symptoms associated with “long COVID” were headache, fatigue, muscle aches/myalgia, articular pains, cognitive impairment, loss of concentration, and loss of smell. Additionally, the subjects showed significant levels of insomnia (p < 0.05) and an overall reduced quality of life (p < 0.05). Conclusions: The results of the study appear in line with recent publications, but uncertainty regarding the definition and specific features of “long COVID” remains. Further studies are needed in order to better define the clinical presentation of the “long COVID” condition and related targeted treatments.

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Emotion regulation across the psychosis continuum

Development and Psychopathology ◽

10.1017/s0954579418001682 ◽

2019 ◽

Vol 32 (1) ◽

pp. 219-227 ◽

Cited By ~ 2

Author(s):

Hannah C. Chapman ◽

Katherine F. Visser ◽

Vijay A. Mittal ◽

Brandon E. Gibb ◽

Meredith E. Coles ◽

...

Keyword(s):

Emotion Regulation ◽

Psychotic Disorders ◽

Psychiatric Symptoms ◽

Healthy Controls ◽

Community Members ◽

Targeted Treatments ◽

Regulation Strategies ◽

Dose Dependent Decrease ◽

Study Participants ◽

Prodromal Syndrome

AbstractEmotion regulation dysfunction is characteristic of psychotic disorders, but little is known about how the use of specific types of emotion regulation strategies differs across phases of psychotic illness. This information is vital for understanding factors contributing to psychosis vulnerability states and developing targeted treatments. Three studies were conducted to examine emotion regulation across phases of psychosis, which included (a) adolescent community members with psychotic-like experiences (PLEs; n = 262) and adolescents without PLEs (n = 1,226); (b) adolescents who met clinical high-risk criteria for a prodromal syndrome (n = 29) and healthy controls (n = 29); and (c) outpatients diagnosed with schizophrenia or schizoaffective disorder (SZ; n = 61) and healthy controls (n = 67). In each study, participants completed the Emotion Regulation Questionnaire and measures of psychiatric symptoms and functional outcome. The three psychosis groups did not differ from each other in reported use of suppression; however, there was evidence for a vulnerability-related, dose-dependent decrease in reappraisal. Across each sample, a lower use of reappraisal was associated with poorer clinical outcomes. Findings indicate that emotion regulation abnormalities occur across a continuum of psychosis vulnerability and represent important targets for intervention.

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