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Fan Yang, Song Xu, Renwang Liu, Tao Shi, Xiongfei Li, Xuebing Li, Gang Chen, Hongyu Liu, Qinghua Zhou, Jun Chen
Introduction: Neurofibromatosis type 1 (NF1) is a common Mendelian multi-system disorder that is characterized by café-au-lait spots (CLS), axillary freckling, optic glioma and plexiform neurofibroma. Various mutations of the NF1 gene are widely accepted to be the main cause of this disease, while whether there are still certain other modifier genes that could influence the phenotypes of NF1 is our concern. Patients and Methods: One proband and his father are involved, who are characterized by plexiform neurofibroma and cutaneous neurofibroma, respectively...
2018: OncoTargets and Therapy
Marija Dimishkovska, Vjosa Mulliqi Kotori, Zoran Gucev, Svetlana Kocheva, Momir Polenakovic, Dijana Plaseska-Karanfilska
BACKGROUND: Fanconi anemia is a rare autosomal recessive or X-linked disorder characterised by clinical and genetic heterogeneity. Most fanconi anemia patients harbour homozygous or double heterozygous mutations in the FANCA (60-65%), FANCC (10-15%), FANCG (~10%) or FANCD2 (3-6%) genes. We have already reported the FANCA variant c.190-256_283+1680del2040dupC as a founder mutation among Macedonian fanconi anemia patients of Gypsy-like ethnic origin. Here, we present a novel FANCA mutation in two patients from Macedonia and Kosovo...
January 20, 2018: Balkan Medical Journal
Jian Xu, Xue Li, Allison Cole, Zachary Sherman, Wei Du
Hematopoietic stem cells preserve their ability to self-renew and differentiate to different lineages in the bone marrow (BM) niche, which is composed in large part by BM stromal cells. Studies have shown that altered signaling in the BM niche results in leukemia initiation or progression. Fanconi anemia (FA) is an inherited BM failure syndrome associated with extremely high risk of leukemic transformation. By using two FA mouse models, here we have investigated the hematopoiesis-supportive function of FA BM mesenchymal stroma cells (MSCs)...
January 27, 2018: Stem Cells
Yibo Li, Xue Li, Allison Cole, Sarah McLaughlin, Wei Du
Icraiin (ICA) is a flavonoid glucoside derived from the Epimedium plant genus, which has potent regenerative properties and is used in western medicine to treat impotence. Recently, ICA has generated great interest in improving hepatic stellate cell function and cardiac rejuvenation. However, how this natural component functions in hematopoiesis remains unexplored. Here we have examined the role of ICA on hematopoietic stem cells (HSCs) using the cancer-prone disease model of Fanconi anemia (FA), an inherited bone marrow failure syndrome with extremely high risk of leukemic predisposition...
January 22, 2018: Cell Cycle
Yao Yu, Hao Hu, Jiun-Sheng Chen, Fulan Hu, Jerry Fowler, Paul Scheet, Hua Zhao, Chad D Huff
While a number of genes have been implicated in melanoma susceptibility, the role of protein-coding variation in melanoma development and progression remains underexplored. To better characterize the role of germline coding variation in melanoma, we conducted a whole-exome case-control and somatic-germline interaction study involving 322 skin cutaneous melanoma cases from The Cancer Genome Atlas and 3607 controls of European ancestry. We controlled for cross-platform technological stratification using XPAT and conducted gene-based association tests using VAAST 2...
January 6, 2018: Biochimica et Biophysica Acta
Ilgin Cagnan, Aysen Gunel-Ozcan, Fatima Aerts-Kaya, Najim Ameziane, Baris Kuskonmaz, Josephine Dorsman, Fatma Gumruk, Duygu Uckan
Transforming growth factor beta (TGF-β) secretion from cells in the bone marrow (BM) niche affects hematopoietic stem cell (HSC) fate and has a cardinal role in HSC quiescence. BM mesenchymal stem cells (BM-MSCs), a component of the BM niche, may produce abnormal levels of TGF-β in Fanconi anemia (FA) and may play a role in bone marrow failure. Here, we molecularly and cellularly characterized FA BM-MSCs by addressing their immunophenotype, proliferation- and differentiation- capacity, reactive oxygen species (ROS) production, senescence activity as well as expression and secretion levels of TGF-β isoforms...
December 15, 2017: Stem Cell Reviews
Yuta Horiuchi, Jason Lin, Yui Shinojima, Kyoko Fujiwara, Mitsuhiko Moriyama, Hiroki Nagase
As more than 80% of hepatocellular carcinoma patients in Japan also suffer from hepatitis C virus infections some time in their medical history, identifying genetic aberrations associated to hepatitis C virulence in these individuals remains a high priority in the diagnosis and treatment of hepatocellular carcinoma. From the BioBank Japan Project, we acquired 480 subjects of hepatocellular carcinoma, chronic hepatitis and liver cirrhosis, and genotyped 131 clinically relevant host single nucleotide polymorphisms to survey the potential association between certain risk alleles and genes to a patient's predisposition to hepatitis C and liver cancer...
February 2018: International Journal of Oncology
Flavia Zita Francies, Rosalind Wainwright, Janet Poole, Kim De Leeneer, Ilse Coene, Greet Wieme, Hélène A Poirel, Bénédicte Brichard, Stephanie Vermeulen, Anne Vral, Jacobus Slabbert, Kathleen Claes, Ans Baeyens
Fanconi Anaemia (FA) is an autosomal recessive disorder characterised by defects in DNA repair, associated with chromosomal instability and cellular hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC). The FA repair pathway involves complex DNA repair mechanisms crucial for genomic stability. Deficiencies in DNA repair genes give rise to chromosomal radiosensitivity. FA patients have shown increased clinical radiosensitivity by exhibiting adverse normal tissue side-effects. The study aimed to investigate chromosomal radiosensitivity of homozygous and heterozygous carriers of FA mutations using three micronucleus (MN) assays...
November 8, 2017: DNA Repair
Danielle C Kimble, Francis P Lach, Siobhan Q Gregg, Frank X Donovan, Elizabeth K Flynn, Aparna Kamat, Alice Young, Meghana Vemulapalli, James W Thomas, James C Mullikin, Arleen D Auerbach, Agata Smogorzewska, Settara C Chandrasekharappa
Fanconi anemia (FA) is a rare recessive DNA repair deficiency resulting from mutations in one of at least 22 genes. Two-thirds of FA families harbor mutations in FANCA. To genotype patients in the International Fanconi Anemia Registry (IFAR) we employed multiple methodologies, screening 216 families for FANCA mutations. We describe identification of 57 large deletions and 261 sequence variants, in 159 families. All but seven families harbored distinct combinations of two mutations demonstrating high heterogeneity...
November 2, 2017: Human Mutation
Rui Zhang, Chang Liu, Yahan Niu, Ying Jing, Haiyang Zhang, Jin Wang, Jie Yang, Ke Zen, Junfeng Zhang, Chen-Yu Zhang, Donghai Li
The DNA damage response is critical for maintaining genome integrity and preventing damage to DNA due to endogenous and exogenous insults. Mitomycin C (MMC), a potent DNA cross-linker, is used as a chemotherapeutic agent because it causes DNA inter-strand cross-links (DNA ICLs) in cancer cells. While many microRNAs, which may serve as oncogenes or tumor suppressors, are grossly dysregulated in human cancers, little is known about their roles in MMC-treated lung cancer. Here, we report that miR-128-3p can attenuate repair of DNA ICLs by targeting SPTAN1 (αII Sp), resulting in cell cycle arrest and promoting chromosomal aberrations in lung cancer cells treated with MMC...
August 29, 2017: Oncotarget
Begoña Diez, Pietro Genovese, Francisco J Roman-Rodriguez, Lara Alvarez, Giulia Schiroli, Laura Ugalde, Sandra Rodriguez-Perales, Julian Sevilla, Cristina Diaz de Heredia, Michael C Holmes, Angelo Lombardo, Luigi Naldini, Juan Antonio Bueren, Paula Rio
Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem cells (HSCs). In our first experiments, we showed that zinc finger nuclease (ZFN)-mediated insertion of a non-therapeutic EGFP-reporter donor in the AAVS1 "safe harbor" locus of FA-A lymphoblastic cell lines (LCLs), indicating that FANCA is not essential for the editing of human cells...
November 2017: EMBO Molecular Medicine
Farah Md Chequer, Vinicius P Venancio, Mara R Almeida, Alexandre F Aissa, Maria Lourdes P Bianchi, Lusânia Mg Antunes
Erythrosine B (ErB) is a cherry pink food colorant and is widely used in foods, drugs, and cosmetics. Quinoline yellow (QY) is a chinophthalon derivative used in cosmetic compositions for application to the skin, lips, and/or body surface. Previously, ErB and QY synthetic dyes were found to induce DNA damage in HepG2 cells. The aim of this study was to investigate the molecular basis underlying the genotoxicity attributed to ErB and QY using the RT(2) Profiler polymerase chain reaction array and by analyzing the expression profile of 84 genes involved in cell cycle arrest, apoptosis, and DNA repair in HepG2 cells...
October 2017: Toxicology and Industrial Health
Lucy Shapiro, Sumana Chatterjee, Dina G Ramadan, Kate M Davies, Martin O Savage, Louise A Metherell, Helen L Storr
BACKGROUND: GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown. OBJECTIVE: To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect...
December 2017: European Journal of Endocrinology
David C Wilkes, Verena Sailer, Hui Xue, Hongwei Cheng, Colin C Collins, Martin Gleave, Yuzhuo Wang, Francesca Demichelis, Himisha Beltran, Mark A Rubin, David S Rickman
Defects in genes involved in DNA damage repair (DDR) pathway are emerging as novel biomarkers and targets for new prostate cancer drug therapies. A previous report revealed an association between an exceptional response to cisplatin treatment and a somatic loss of heterozygosity (LOH) of FANCA in a patient with metastatic prostate cancer who also harbored a germline FANCA variant (S1088F). Although germline FANCA mutations are the most frequent alterations in patients with Fanconi anemia, germline alterations are less common in prostate cancer...
September 2017: Cold Spring Harbor Molecular Case Studies
Massimo Bogliolo, Dominique Bluteau, James Lespinasse, Roser Pujol, Nadia Vasquez, Catherine Dubois d'Enghien, Dominique Stoppa-Lyonnet, Thierry Leblanc, Jean Soulier, Jordi Surrallés
PurposeMutations in genes involved in Fanconi anemia (FA)/BRCA DNA repair pathway cause cancer susceptibility diseases including familial breast cancer and Fanconi anemia (FA). A single FA patient with biallelic FANCM mutations was reported in 2005 but concurrent FANCA pathogenic mutations precluded assignment of FANCM as an FA gene. Here we report three individuals with biallelic FANCM truncating mutations who developed early-onset cancer and toxicity to chemotherapy but did not present congenital malformations or any hematological phenotype suggestive of FA...
August 24, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Maria Fernandez-Garcia, Maria Lamana Luzuriaga, Miriam Hernando-Rodriguez, Rebeca Sanchez-Dominguez, Juan Bueren, Rosa Yañez
In this study we propose a novel approach based on the use of mesenchymal stromal cells (MSC) aiming at limiting risks of graft failure in gene therapy protocols associated with low conditioning regimens. Because the engraftment of corrected hematopoietic stem cells (HSCs) is particularly challenging in Fanconi anemia (FA), we have investigated the relevance of MSCs in an experimental model of FA gene therapy. Our results firstly showed that risks of graft failure in recipients conditioned with a moderate dose of 5Gy and infused with limited numbers of WT HSCs are significantly higher in Fanca-/- recipients as compared to WT recipients...
August 17, 2017: Human Gene Therapy
Paula Río, Susana Navarro, Guillermo Guenechea, Rebeca Sánchez-Domínguez, Maria Luisa Lamana, Rosa Yañez, Jose A Casado, Parinda A Mehta, Maria Roser Pujol, Jordi Surrallés, Sabine Charrier, Anne Galy, José C Segovia, Cristina Díaz de Heredia, Julián Sevilla, Juan A Bueren
Previous Fanconi anemia (FA) gene therapy studies have failed to demonstrate engraftment of gene-corrected hematopoietic stem and progenitor cells (HSPCs) from FA patients, either after autologous transplantation or infusion into immunodeficient mice. In this study, we demonstrate that a validated short transduction protocol of G-CSF plus plerixafor-mobilized CD34(+) cells from FA-A patients with a therapeutic FANCA-lentiviral vector corrects the phenotype of in vitro cultured hematopoietic progenitor cells...
September 28, 2017: Blood
Andrea Necchi, Bernhard J Eigl, Eddy Shih-Hsin Yang, Sejong Bae, Darshan Chandrashekar, Dongquan Chen, Gurudatta Naik, Amitkumar Mehta, Patrizia Giannatempo, Maurizio Colecchia, Jennifer Gordetsky, Shi Wei, Tiffiny Cooper, Sooryanarayana Varambally, Guru Sonpavde
In men with advanced penile squamous cell carcinoma receiving first-line chemotherapy, visceral metastases (VM) and Eastern Cooperative Oncology Group performance status ≥1 are poor prognostic factors for overall survival (OS). We hypothesized that tumor gene expression profiling may enhance prognostic stratification and identify potential therapeutic targets. In this retrospective study, RNA extracted from macrodissected tumors underwent profiling for the expression of 738 genes using NanoString. Univariate and multivariate analyses assessed the association of genes, VM, and performance status with OS...
August 27, 2016: European Urology Focus
Daniela V Pilonetto, Noemi F Pereira, Carmem M S Bonfim, Lisandro L Ribeiro, Marco A Bitencourt, Lianne Kerkhoven, Karijn Floor, Najim Ameziane, Hans Joenje, Johan J P Gille, Ricardo Pasquini
BACKGROUND: Fanconi anemia (FA) is a predominantly autosomal recessive disease with wide genetic heterogeneity resulting from mutations in several DNA repair pathway genes. To date, 21 genetic subtypes have been identified. We aimed to identify the FA genetic subtypes in the Brazilian population and to develop a strategy for molecular diagnosis applicable to routine clinical use. METHODS: We screened 255 patients from Hospital de Clínicas, Universidade Federal do Paraná for 11 common FA gene mutations...
July 2017: Molecular Genetics & Genomic Medicine
Joshi Niraj, Marie-Christine Caron, Karine Drapeau, Stéphanie Bérubé, Laure Guitton-Sert, Yan Coulombe, Anthony M Couturier, Jean-Yves Masson
Fanconi anemia (FA) is a recessive genetic disorder characterized by congenital abnormalities, progressive bone-marrow failure, and cancer susceptibility. The FA pathway consists of at least 21 FANC genes (FANCA-FANCV), and the encoded protein products interact in a common cellular pathway to gain resistance against DNA interstrand crosslinks. After DNA damage, FANCD2 is monoubiquitinated and accumulates on chromatin. FANCD2 plays a central role in the FA pathway, using yet unidentified DNA binding regions...
August 21, 2017: Nucleic Acids Research
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