Papers by Krinio Giannikou
Frontiers in Genetics, Jan 30, 2023
Fig S2. Nonsynonymous (left panel) and overall (right panel) tumor mutation burden (TMB) for subj... more Fig S2. Nonsynonymous (left panel) and overall (right panel) tumor mutation burden (TMB) for subjects that achieved clinical benefit and those who had no clinical benefit (NCB). TMB for each patient is SNVs/indels per megabase of targeted capture genomic region. The horizontal bars indicate median values. Note that y axis is log scale. Abbreviations: UTUC - upper tract urothelial carcinoma.
Ritanserin inhibits the proliferation of multiple TSC2-deficient cell lines, independently of aut... more Ritanserin inhibits the proliferation of multiple TSC2-deficient cell lines, independently of autophagy.
Lipidomic analysis of ritanserin treated Tsc2-deficient cells
Purine metabolism following ritanserin treatment in Tsc2-deficient cells
Ritanserin inhibits macropinocytosis and acidic organelle homeostasis in TSC2-deficient cells
Table S1. Massively Parallel Sequencing (MPS) metrics and cancer sample characteristics.
Table S2. Demographic and clinical characteristics of 30 cancer patients with mTOR pathway mutati... more Table S2. Demographic and clinical characteristics of 30 cancer patients with mTOR pathway mutations. S2.1. Master table showing a summary of demographic characteristics and clinical outcomes. S2.2. Prior systemic treatment regimens. S2.3. Objective response to everolimus according to RECIST v1.1 criteria. S2.4. Toxicity profile of patients according to CTCAE v4.0.
Purine metabolism following ritanserin treatment in Tsc2-deficient cells
Lipidomic analysis of ritanserin treated Tsc2-deficient cells
Ritanserin inhibits the proliferation of multiple TSC2-deficient cell lines, independently of aut... more Ritanserin inhibits the proliferation of multiple TSC2-deficient cell lines, independently of autophagy.
Lymphangioleiomyomatosis is a rare destructive lung disease affecting primarily women and is the ... more Lymphangioleiomyomatosis is a rare destructive lung disease affecting primarily women and is the primary lung manifestation of tuberous sclerosis complex (TSC). In lymphangioleiomyomatosis, biallelic loss of TSC1/2 leads to hyperactivation of mTORC1 and inhibition of autophagy. To determine how the metabolic vulnerabilities of TSC2-deficient cells can be targeted, we performed a high-throughput screen utilizing the “Repurposing” library at the Broad Institute of MIT and Harvard (Cambridge, MA), with or without the autophagy inhibitor chloroquine. Ritanserin, an inhibitor of diacylglycerol kinase alpha (DGKA), was identified as a selective inhibitor of proliferation of Tsc2−/− mouse embryonic fibroblasts (MEF), with no impact on Tsc2+/+ MEFs. DGKA is a lipid kinase that metabolizes diacylglycerol to phosphatidic acid, a key component of plasma membranes. Phosphatidic acid levels were increased 5-fold in Tsc2−/− MEFs compared with Tsc2+/+ MEFs, and treatment of Tsc2−/− MEFs with ritan...
Ritanserin inhibits macropinocytosis and acidic organelle homeostasis in TSC2-deficient cells
Purpose:This was a multicenter, histology-agnostic, single-arm prospective phase II trial of ther... more Purpose:This was a multicenter, histology-agnostic, single-arm prospective phase II trial of therapeutic activity of everolimus, an oral mTORC1 inhibitor, in patients with advanced solid tumors that harbored TSC1/TSC2 or MTOR mutations.Patients and Methods:Patients with tumors with inactivating TSC1/TSC2 or activating MTOR mutations identified in any Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. Patients were treated with everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Whole-exome sequencing was performed to identify co-occurring genomic alterations.Results:Between November 2015 and October 2018, 30 patients were enrolled at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Tumors harbored TSC1 (13/30), TSC2 (15/30), concurrent TSC1 and TSC2 (1/30), or MTOR (1/30) mutations. The most common treatment-related adverse event of any grade...
Intellectual Disability (ID) is a very clinically and genetically heterogeneous neurodevelopmenta... more Intellectual Disability (ID) is a very clinically and genetically heterogeneous neurodevelopmental entity, thus raising difficulties on genetic evaluation and diagnosis. Hitherto, only a few cases are detected by conventional cytogenetic and molecular techniques, while most cases remain undiagnosed and require further investigation.The present study focuses on the clinical application of array-CGH for first time in Greece as a first-tier diagnostic tool for the investigation of genetic basis of unknown etiology ID in order to identify novel pathogenic copy number variations (CNVs) and causal ID genes. All patients were referred for genetic testing by paediatricians, pediatric neurologists and auxologists from various pediatric hospitals in the whole country and/or by private doctors. Overall, 235 patients with variable degrees of ID underwent array-CGH analysis in the Department of Medical Genetics, University of Athens. They had previously undergone a series of other genetic tests ...
Annual Review of Genomics and Human Genetics, Aug 31, 2022
Journal of Clinical Oncology
11552 Background: Malignant perivascular epithelioid cell tumor (PEComa) and leiomyosarcoma (LMS)... more 11552 Background: Malignant perivascular epithelioid cell tumor (PEComa) and leiomyosarcoma (LMS) are two sarcomas with overlapping morphologic and immunophenotypic features which can make their diagnostic distinction challenging. We aimed to characterize the transcriptional and epigenetic landscape of PEComa and LMS to identify distinguishing features. Methods: We performed whole transcriptome RNA-sequencing on 19 PEComas and compared their gene expression profile to 259 sarcomas from The Cancer Genome Atlas (TCGA) including 104 LMS. ChIP-sequencing for H3K27ac, a histone modification associated with activation of nearby genes/open chromatin, was conducted on 9 malignant PEComas and 12 LMS and were compared with publicly available data from 4 other sarcoma subtypes (chordoma; osteosarcoma; undifferentiated pleomorphic sarcoma; rhabdomyosarcoma; n = 29 tumors). Results: Genome-wide epigenetic and transcriptional analyses revealed overlapping patterns between PEComa and LMS, which we...
Journal of Clinical Oncology
e16532 Background: Mutation and inactivation of the tumor suppressor gene TSC1 is a recurrent (6-... more e16532 Background: Mutation and inactivation of the tumor suppressor gene TSC1 is a recurrent (6-10%) event in bladder cancer, but whether it functions as a driver event for tumor development has been uncertain. Methods: We performed differential gene expression and pathway analyses using RNA-seq data from the curated TCGA TSC1 mutant BLCA (n = 26) and TSC1 wild-type BLCA (n = 382) cohort and compared to an internal cohort of putative TSC1/TSC2-driven tumors (n = 63). Mechanistic studies, as well as RNA-seq and H3K27ac ChIP-seq analyses, were conducted in 2 TSC1 mutant/WT BLCA cell lines. Results: Comparison of The Cancer Genome Atlas (TCGA) TSC1-mutant bladder cancers ( TSC1mBLCA) with TCGA TSC1 wildtype tumors ( TSC1WTBLCA) identified a conserved TSC-associated expression signature, similar to ones seen in syndromic TSC tumors. GSEA and DESeq2 analyses implicated both mTORC1 hyperactivation, as well as activation of lysosomal pathways in TSC1mBLCA. We validated our findings by IHC...
Η Νοητική Υστέρηση (ΝΥ) αποτελεί μια πολυπαραγοντική νευροαναπτυξιακή διαταραχή με μεγάλη κλινική... more Η Νοητική Υστέρηση (ΝΥ) αποτελεί μια πολυπαραγοντική νευροαναπτυξιακή διαταραχή με μεγάλη κλινική και γενετική ετερογένεια που καθιστά δύσκολη τη γενετική εκτίμηση και διάγνωση. Μέχρι σήμερα, λίγες περιπτώσεις διαλευκάνονται με τις συμβατικές κυτταρογενετικές και μοριακές τεχνικές, ενώ οι περισσότερες παραμένουν αδιάγνωστες και απαιτούν περαιτέρω διερεύνηση. Η παρούσα μελέτη επικεντρώνεται στην εφαρμογή -για πρώτη φορά στην Ελλάδα- των μικροσυστοιχιών array-CGH για τη διερεύνηση του γενετικού υποβάθρου της ΝΥ αγνώστου αιτιολογίας προκειμένου να εντοπιστούν κλινικά σημαντικές ποικιλομορφίες αριθμού αντιγράφου (CNVs) και νέα παθολογικά γονίδια. Μελετήθηκαν συνολικά 235 ασθενείς με ποικίλου βαθμού ΝΥ αγνώστου αιτιολογίας με αρνητικό αποτέλεσμα από άλλες γενετικές εξετάσεις (όπως κλασικό καρυότυπο, Χ-Fra, PWS/AS, RETT ,κα) (Eργαστήριο Ιατρικής Γενετικής, ΕΚΠΑ). Όλοι οι ασθενείς παραπέμφθηκαν για γενετικό έλεγχο από παιδιάτρους, παιδονευρολόγους και αναπτυξιολόγους από διάφορα παιδιατρικ...
Journal of Clinical Investigation
BACKGROUND. Tuberous sclerosis complex (TSC) is a neurogenetic syndrome due to loss-of-function m... more BACKGROUND. Tuberous sclerosis complex (TSC) is a neurogenetic syndrome due to loss-of-function mutations in TSC2 or TSC1, characterized by tumors at multiple body sites, including facial angiofibroma (FAF). Here, an ultrasensitive assessment of the extent and range of UV-induced mutations in TSC facial skin was performed. METHODS. A multiplex high-sensitivity PCR assay (MHPA) was developed, enabling mutation detection at extremely low (<0.1%) variant allele frequencies (VAFs). RESULTS. MHPA assays were developed for both TSC2 and TP53, and applied to 81 samples, including 66 skin biopsies. UV-induced second-hit mutation causing inactivation of TSC2 was pervasive in TSC facial skin with an average of 4.8 mutations per 2-mm biopsy at median VAF 0.08%, generating more than 150,000 incipient facial tumors (subclinical "micro-FAFs") in the average TSC subject. The MHPA analysis also led to the identification of a refined UV-related indel signature and a recurrent complex mutation pattern, consisting of both a single-nucleotide or dinucleotide variant and a 1-to 9-nucleotide deletion, in cis. CONCLUSION. TSC facial skin can be viewed as harboring a patchwork of clonal fibroblast proliferations (micro-FAFs) with indolent growth, a small proportion of which develop into clinically observable FAF. Our observations also expand the spectrum of UV-related mutation signatures.
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Papers by Krinio Giannikou