Publications by authors named "Kaya Bilguvar"

124 Publications

The genetic structure of the Turkish population reveals high levels of variation and admixture.

Proc Natl Acad Sci U S A 2021 Sep;118(36)

Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey;

The construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes ( = 2,589) or whole genomes ( = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 50% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes.
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http://dx.doi.org/10.1073/pnas.2026076118DOI Listing
September 2021

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19.

Sci Immunol 2021 08;6(62)

Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such variants ( = 3.5 × 10). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (=2, 5 and 38 years), or moderate (=1, 5 years), severe (=1, 27 years), or critical (=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious variants in the male general population is < 6.5x10 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.
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http://dx.doi.org/10.1126/sciimmunol.abl4348DOI Listing
August 2021

Autoantibodies neutralizing type I IFNs are present in 4% of uninfected individuals over 70 years old and account for 20% of COVID-19 deaths.

Sci Immunol 2021 08;6(62)

Joint Research Unit, Hospices Civils de Lyon-bio Mérieux, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France; International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France.

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.
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http://dx.doi.org/10.1126/sciimmunol.abl4340DOI Listing
August 2021

Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy.

Genet Med 2021 Aug 12. Epub 2021 Aug 12.

Texas Children's Hospital, Houston, TX, USA.

Purpose: Alternative splicing plays a critical role in mouse neurodevelopment, regulating neurogenesis, cortical lamination, and synaptogenesis, yet few human neurodevelopmental disorders are known to result from pathogenic variation in splicing regulator genes. Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a ubiquitously expressed splicing regulator not known to underlie a Mendelian disorder.

Methods: Exome sequencing and rare variant family-based genomics was performed as a part of the Baylor-Hopkins Center for Mendelian Genomics Initiative. Additional families were identified via GeneMatcher.

Results: We identified six patients from three unrelated families with homozygous loss-of-function variants in NSRP1. Clinical features include developmental delay, epilepsy, variable microcephaly (Z-scores -0.95 to -5.60), hypotonia, and spastic cerebral palsy. Brain abnormalities included simplified gyral pattern, underopercularization, and/or vermian hypoplasia. Molecular analysis identified three pathogenic NSRP1 predicted loss-of-function variant alleles: c.1359_1362delAAAG (p.Glu455AlafsTer20), c.1272dupG (p.Lys425GlufsTer5), and c.52C>T (p.Gln18Ter). The two frameshift variants result in a premature termination codon in the last exon, and the mutant transcripts are predicted to escape nonsense mediated decay and cause loss of a C-terminal nuclear localization signal required for NSRP1 function.

Conclusion: We establish NSRP1 as a gene for a severe autosomal recessive neurodevelopmental disease trait characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.
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http://dx.doi.org/10.1038/s41436-021-01291-xDOI Listing
August 2021

Mutation in Leads to Hypotonic Cerebral Palsy, Autism, Epilepsy, and Intellectual Disability.

Neurol Genet 2021 Aug 29;7(4):e602. Epub 2021 Jul 29.

Pediatric Movement Disorders Program (S.A.L., S.B., J.H., J.L., S.R.P.-L., M.C.K.), Barrow Neurological Institute, Phoenix Children's Hospital; Departments of Child Health, Neurology, Genetics and Cellular & Molecular Medicine (S.A.L., S.B., J.L., S.R.P.-L., M.C.K.), University of Arizona College of Medicine; Division of Neuroradiology (P.C.), Department of Radiology, Phoenix Children's Hospital, AZ; Programs in Neuroscience and Molecular & Cellular Biology (A.H., A.M.), Arizona State University, Tempe; and Department of Genetics (S.C.J.), Washington University, St. Louis, MO; Department of Genetics (K.B.), Yale University, New Haven, CT.

Objective: To determine whether mutations reported for can cause mixed neurodevelopmental disorders, we performed both functional studies on variant pathogenicity and ZDHHC15 function in animal models.

Methods: We examined protein function of 4 identified variants in ZDHHC15 in a yeast complementation assay and locomotor defects of loss-of-function genotypes in a model.

Results: Although we assessed multiple patient variants, only 1 (p.H158R) affected protein function. We report a patient with a diagnosis of hypotonic cerebral palsy, autism, epilepsy, and intellectual disability associated with this bona fide damaging X-linked variant. Features include tall forehead with mild brachycephaly, down-slanting palpebral fissures, large ears, long face, facial muscle hypotonia, high-arched palate with dental crowding, and arachnodactyly. The patient had mild diminished cerebral volume, with left-sided T2/FLAIR hyperintense periatrial ovoid lesion. We found that loss-of-function mutations in orthologs of this gene cause flight and coordinated movement defects in .

Conclusions: Our findings support a functional expansion of this gene to a role in motor dysfunction. Although mutations represent a rare cause of neurodevelopmental disability, candidate variants need to be carefully assessed before pathogenicity can be determined.
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http://dx.doi.org/10.1212/NXG.0000000000000602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323736PMC
August 2021

Combining genomic and epidemiological data to compare the transmissibility of SARS-CoV-2 lineages.

medRxiv 2021 Jul 2. Epub 2021 Jul 2.

Emerging SARS-CoV-2 variants have shaped the second year of the COVID-19 pandemic and the public health discourse around effective control measures. Evaluating the public health threat posed by a new variant is essential for appropriately adapting response efforts when community transmission is detected. However, this assessment requires that a true comparison can be made between the new variant and its predecessors because factors other than the virus genotype may influence spread and transmission. In this study, we develop a framework that integrates genomic surveillance data to estimate the relative effective reproduction number (R ) of co-circulating lineages. We use Connecticut, a state in the northeastern United States in which the SARS-CoV-2 variants B.1.1.7 and B.1.526 co-circulated in early 2021, as a case study for implementing this framework. We find that the R of B.1.1.7 was 6-10% larger than that of B.1.526 in Connecticut in the midst of a COVID-19 vaccination campaign. To assess the generalizability of this framework, we apply it to genomic surveillance data from New York City and observe the same trend. Finally, we use discrete phylogeography to demonstrate that while both variants were introduced into Connecticut at comparable frequencies, clades that resulted from introductions of B.1.1.7 were larger than those resulting from B.1.526 introductions. Our framework, which uses open-source methods requiring minimal computational resources, may be used to monitor near real-time variant dynamics in a myriad of settings.
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http://dx.doi.org/10.1101/2021.07.01.21259859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259915PMC
July 2021

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.

Brain 2021 06;144(5):1422-1434

Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.
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http://dx.doi.org/10.1093/brain/awab041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219359PMC
June 2021

Genetic Defects in Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice.

Front Cell Dev Biol 2021 23;9:662903. Epub 2021 Apr 23.

Department of Cellular and Molecular Physiology, Yale School of Medicine, Yale University, New Haven, CT, United States.

Asthenozoospermia accounts for over 80% of primary male infertility cases. Reduced sperm motility in asthenozoospermic patients are often accompanied by teratozoospermia, or defective sperm morphology, with varying severity. Multiple morphological abnormalities of the flagella (MMAF) is one of the most severe forms of asthenoteratozoospermia, characterized by heterogeneous flagellar abnormalities. Among various genetic factors known to cause MMAF, multiple variants in the gene are reported to underlie MMAF in humans. However, the pathogenicity by DNAH2 mutations remains largely unknown. In this study, we identified a novel recessive variant (NM_020877:c.12720G > T;p.W4240C) in by whole-exome sequencing, which fully co-segregated with the infertile male members in a consanguineous Pakistani family diagnosed with asthenozoospermia. 80-90% of the sperm from the patients are morphologically abnormal, and analysis models reveal that the non-synonymous variant substitutes a residue in dynein heavy chain domain and destabilizes DNAH2. To better understand the pathogenicity of various variants underlying MMAF in general, we functionally characterized -mutant mice generated by CRISPR/Cas9 genome editing. -null males, but not females, are infertile. -null sperm cells display absent, short, bent, coiled, and/or irregular flagella consistent with the MMAF phenotype. We found misexpression of centriolar proteins and delocalization of annulus proteins in -null spermatids and sperm, suggesting dysregulated flagella development in spermiogenesis. Scanning and transmission electron microscopy analyses revealed that flagella ultrastructure is severely disorganized in -null sperm. Absence of DNAH2 compromises the expression of other axonemal components such as DNAH1 and RSPH3. Our results demonstrate that DNAH2 is essential for multiple steps in sperm flagella formation and provide insights into molecular and cellular mechanisms of MMAF pathogenesis.
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http://dx.doi.org/10.3389/fcell.2021.662903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103034PMC
April 2021

Recessive Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.

Neurol Genet 2021 Jun 22;7(3):e583. Epub 2021 Apr 22.

Pediatric Movement Disorders Program (S.B., B.S.G., M.C.K.), Barrow Neurological Institute, Phoenix Children's Hospital, AZ; Departments of Child Health (S.B., B.S.G., M.C.K.), Neurology, Genetics, and Cellular & Molecular Medicine, University of Arizona College of Medicine Phoenix, Phoenix, AZ; Iranian Center of Neurological Research (A.T., H.D.), Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Genetics (S.C.J.), Washington University School of Medicine, St. Louis, MO; Student Research Committee (E.A.), School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Genetics Research Center (S.F.), University of Social Welfare and Rehabilitation Sciences, Tehran, Iran; Department of Genetics (K.B.), Yale University, New Haven, CT; and Department of Paediatrics (M.C.F.), Monash University, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1212/NXG.0000000000000583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077768PMC
June 2021

Integrated mutational landscape analysis of uterine leiomyosarcomas.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

Department of Pathology, University of Brescia, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, 25100 Brescia, Italy.

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; = 0.002), GS-626510 (C-MYC/BETi; < 0.000001 and = 0.0005), and copanlisib (PIK3CAi; = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.
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http://dx.doi.org/10.1073/pnas.2025182118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053980PMC
April 2021

Resolution of sclerotic lesions of dysosteosclerosis due to biallelic SLC29A3 variant in a Turkish girl.

Am J Med Genet A 2021 07 10;185(7):2271-2277. Epub 2021 Apr 10.

Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey.

Dysosteosclerosis is a group of sclerosing bone dysplasia characterized by short stature, increased bone fragility, osteosclerosis, and platyspondyly. It is a genetically heterogeneous disorder caused by biallelic mutations in the SLC29A3, TNFRSF11A, TCIRG1, and CSF1R genes. To date, four dysosteosclerosis patients with SLC29A3 mutations have been reported. Here, we report biallelic SLC29A3 (c.303_320dupCTACTTTGAGAGCTACCT) variant in a three-year-old girl. She had large anterior fontanelle, fracture history, short stature, camptodactyly, elbow contracture, and melanocytic nevus. Initial skeletal radiographs revealed platyspondyly, dense vertebral endplates (sandwich appearance of the vertebral bodies), diffuse sclerosis of the peripheral side of the pelvic bones, sclerosis of metaphysis and diaphysis of the long bones, metaphyseal widening, and diaphyseal cortical thickening. Mild sclerosis was also present in the skull base, maxilla, rib, scapula, and phalanges. Notably, we observed that sandwich vertebrae appearance significantly resolved and sclerosis of ribs, scapula, pelvis, and long bone metaphysis regressed over a 2.5-year period. However, platyspondyly, metaphyseal widening, and diaphyseal cortical thickening persisted. In conclusion, this study demonstrates spontaneous resolution of osteosclerosis, which was not described previously in patients with dysosteosclerosis.
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http://dx.doi.org/10.1002/ajmg.a.62198DOI Listing
July 2021

ALG13 X-linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes.

J Inherit Metab Dis 2021 Jul 26;44(4):1001-1012. Epub 2021 Mar 26.

Department of Biochemistry, St. George's University School of Medicine, St. George's, Grenada.

Pathogenic variants in ALG13 (ALG13 UDP-N-acetylglucosaminyltransferase subunit) cause an X-linked congenital disorder of glycosylation (ALG13-CDG) where individuals have variable clinical phenotypes that include developmental delay, intellectual disability, infantile spasms, and epileptic encephalopathy. Girls with a recurrent de novo c.3013C>T; p.(Asn107Ser) variant have normal transferrin glycosylation. Using a highly sensitive, semi-quantitative flow injection-electrospray ionization-quadrupole time-of-flight mass spectrometry (ESI-QTOF/MS) N-glycan assay, we report subtle abnormalities in N-glycans that normally account for <0.3% of the total plasma glycans that may increase up to 0.5% in females with the p.(Asn107Ser) variant. Among our 11 unrelated ALG13-CDG individuals, one male had abnormal serum transferrin glycosylation. We describe seven previously unreported subjects including three novel variants in ALG13 and report a milder neurodevelopmental course. We also summarize the molecular, biochemical, and clinical data for the 53 previously reported ALG13-CDG individuals. We provide evidence that ALG13 pathogenic variants may mildly alter N-linked protein glycosylation in both female and male subjects, but the underlying mechanism remains unclear.
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http://dx.doi.org/10.1002/jimd.12378DOI Listing
July 2021

Sequential filtering for clinically relevant variants as a method for clinical interpretation of whole exome sequencing findings in glioma.

BMC Med Genomics 2021 02 23;14(1):54. Epub 2021 Feb 23.

Department of Neurosurgery, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Altunizade Mahallesi, Yurtcan Sok. No:1, Üsküdar, Istanbul, 34662, Turkey.

Background: In the clinical setting, workflows for analyzing individual genomics data should be both comprehensive and convenient for clinical interpretation. In an effort for comprehensiveness and practicality, we attempted to create a clinical individual whole exome sequencing (WES) analysis workflow, allowing identification of genomic alterations and presentation of neurooncologically-relevant findings.

Methods: The analysis workflow detects germline and somatic variants and presents: (1) germline variants, (2) somatic short variants, (3) tumor mutational burden (TMB), (4) microsatellite instability (MSI), (5) somatic copy number alterations (SCNA), (6) SCNA burden, (7) loss of heterozygosity, (8) genes with double-hit, (9) mutational signatures, and (10) pathway enrichment analyses. Using the workflow, 58 WES analyses from matched blood and tumor samples of 52 patients were analyzed: 47 primary and 11 recurrent diffuse gliomas.

Results: The median mean read depths were 199.88 for tumor and 110.955 for normal samples. For germline variants, a median of 22 (14-33) variants per patient was reported. There was a median of 6 (0-590) reported somatic short variants per tumor. A median of 19 (0-94) broad SCNAs and a median of 6 (0-12) gene-level SCNAs were reported per tumor. The gene with the most frequent somatic short variants was TP53 (41.38%). The most frequent chromosome-/arm-level SCNA events were chr7 amplification, chr22q loss, and chr10 loss. TMB in primary gliomas were significantly lower than in recurrent tumors (p = 0.002). MSI incidence was low (6.9%).

Conclusions: We demonstrate that WES can be practically and efficiently utilized for clinical analysis of individual brain tumors. The results display that NOTATES produces clinically relevant results in a concise but exhaustive manner.
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http://dx.doi.org/10.1186/s12920-021-00904-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903763PMC
February 2021

Neuroinvasion of SARS-CoV-2 in human and mouse brain.

J Exp Med 2021 03;218(3)

Sorbonne Université, INSERM U1127, French National Centre for Scientific Research, Joint Research Unit 7225, Paris Brain Institute, Institut du Cerveau et de la Moelle Épinière, Paris, France.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
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http://dx.doi.org/10.1084/jem.20202135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808299PMC
March 2021

Mutations and Copy Number Alterations in Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms.

Biomedicines 2020 Dec 7;8(12). Epub 2020 Dec 7.

Department of Neurosurgery, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey.

Little is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but -mutant gliomas as well as diffuse midline gliomas -K27M were excluded to search for the possible presence of new entities among the very heterogenous group of -WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including promoter mutations, 7/10 pattern, or -amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and "Others" differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA.
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http://dx.doi.org/10.3390/biomedicines8120574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762325PMC
December 2020

Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.

Am J Med Genet A 2021 01 24;185(1):119-133. Epub 2020 Oct 24.

Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey.

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.
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http://dx.doi.org/10.1002/ajmg.a.61926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197629PMC
January 2021

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Nat Med 2020 11 19;26(11):1754-1765. Epub 2020 Oct 19.

Departments of Neurosurgery, Engineering Science & Mechanics, and Physics; Center for Neural Engineering and Infectious Disease Dynamics, The Pennsylvania State University, University Park, PA, USA.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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http://dx.doi.org/10.1038/s41591-020-1090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871900PMC
November 2020

Associations of meningioma molecular subgroup and tumor recurrence.

Neuro Oncol 2021 05;23(5):783-794

Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.

Background: We and others have identified mutually exclusive molecular subgroups of meningiomas; however, the implications of this classification for clinical prognostication remain unclear. Integrated genomic and epigenomic analyses implicate unique oncogenic processes associated with each subgroup, suggesting the potential for divergent clinical courses. The aim of this study was to understand the associated clinical outcomes of each subgroup, as this could optimize treatment for patients.

Methods: We analyzed outcome data for 469 meningiomas of known molecular subgroup, including extent of resection, postoperative radiation, surveillance imaging, and time to recurrence, when applicable. Statistical relationships between outcome variables and subgroup were assessed. Features previously associated with recurrence were further investigated after stratification by subgroup. We used Kaplan-Meier analyses to compare progression-free survival, and identified factors significantly associated with recurrence using Cox proportional hazards modeling.

Results: Meningioma molecular subgroups exhibited divergent clinical courses at 2 years of follow-up, with several aggressive subgroups (NF2, PI3K, HH, tumor necrosis factor receptor-associated factor 7 [TRAF7]) recurring at an average rate of 22 times higher than others (KLF4, POLR2A, SMARCB1). PI3K-activated tumors recurred earlier than other subgroups but had intermediate long-term outcome. Among low-grade tumors, HH and TRAF7 meningiomas exhibited elevated recurrence compared with other subgroups. Recurrence of NF2 tumors was associated with male sex, high grade, and elevated Ki-67. Multivariate analysis identified molecular subgroup as an independent predictor of recurrence, along with grade and previous recurrence.

Conclusion: We describe distinct clinical outcomes and recurrence rates associated with meningioma molecular subgroups. Our findings emphasize the importance of genomic characterization to guide postoperative management decisions for meningiomas.
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http://dx.doi.org/10.1093/neuonc/noaa226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099468PMC
May 2021

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

Nat Genet 2020 10 28;52(10):1046-1056. Epub 2020 Sep 28.

Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
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http://dx.doi.org/10.1038/s41588-020-0695-1DOI Listing
October 2020

Autoantibodies against type I IFNs in patients with life-threatening COVID-19.

Science 2020 10 24;370(6515). Epub 2020 Sep 24.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
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http://dx.doi.org/10.1126/science.abd4585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857397PMC
October 2020

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Science 2020 10 24;370(6515). Epub 2020 Sep 24.

Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
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http://dx.doi.org/10.1126/science.abd4570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857407PMC
October 2020

Neuroinvasion of SARS-CoV-2 in human and mouse brain.

bioRxiv 2020 Sep 8. Epub 2020 Sep 8.

Sorbonne Université, INSERM U1127, CNRS UMR 7225, Paris Brain Institute - ICM, Paris, France.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
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http://dx.doi.org/10.1101/2020.06.25.169946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491522PMC
September 2020

METAP1 mutation is a novel candidate for autosomal recessive intellectual disability.

J Hum Genet 2021 Feb 6;66(2):215-218. Epub 2020 Aug 6.

Department of Neurosurgery, Neurobiology and Genetics, New Haven, CT, 06520-8082, USA.

Intellectual disability (ID) is a genetic and clinically heterogeneous common disease and underlying molecular pathogenesis can frequently not be identified by whole-exome/genome testing. Here, we report four siblings born to a consanguineous union who presented with intellectual disability and discuss the METAP1 pathway as a novel etiology of ID. Genomic analyses demonstrated that patients harbor a novel homozygous nonsense mutation in the gene METAP1. METAP1 codes for methionine aminopeptidase 1 (MetAP1) which oversees the co-translational excision of the first methionine remnants in eukaryotes. The loss-of-function mutations to this gene may result in a defect in the translation of many essential proteins within a cell. Improper neuronal function resulting from this loss of essential proteins could lead to neurologic impairment and ID.
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http://dx.doi.org/10.1038/s10038-020-0820-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785574PMC
February 2021

Human CRY1 variants associate with attention deficit/hyperactivity disorder.

J Clin Invest 2020 07;130(7):3885-3900

Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.

Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.
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http://dx.doi.org/10.1172/JCI135500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324179PMC
July 2020

Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.

Brain 2020 05;143(5):1447-1461

Neurogenetics Group, VIB-Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.
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http://dx.doi.org/10.1093/brain/awaa085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241960PMC
May 2020

Correlations between genomic subgroup and clinical features in a cohort of more than 3000 meningiomas.

J Neurosurg 2019 Oct 25:1-10. Epub 2019 Oct 25.

19Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Objective: Recent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts.

Methods: Targeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher's exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features.

Results: Genomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among "mutation unknown" samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor's underlying driver mutation.

Conclusions: Using a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.
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http://dx.doi.org/10.3171/2019.8.JNS191266DOI Listing
October 2019

Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy.

Proc Natl Acad Sci U S A 2019 11 17;116(45):22730-22736. Epub 2019 Oct 17.

Institute of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models ( = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.
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http://dx.doi.org/10.1073/pnas.1911385116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842590PMC
November 2019
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