%0 Journal Article %J Am J Hum Genet %D 2023 %T Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease. %A Calame, Daniel G %A Guo, Tianyu %A Wang, Chen %A Garrett, Lillian %A Jolly, Angad %A Dawood, Moez %A Kurolap, Alina %A Henig, Noa Zunz %A Fatih, Jawid M %A Herman, Isabella %A Du, Haowei %A Mitani, Tadahiro %A Becker, Lore %A Rathkolb, Birgit %A Gerlini, Raffaele %A Seisenberger, Claudia %A Marschall, Susan %A Hunter, Jill V %A Gerard, Amanda %A Heidlebaugh, Alexis %A Challman, Thomas %A Spillmann, Rebecca C %A Jhangiani, Shalini N %A Coban-Akdemir, Zeynep %A Lalani, Seema %A Liu, Lingxiao %A Revah-Politi, Anya %A Iglesias, Alejandro %A Guzman, Edwin %A Baugh, Evan %A Boddaert, Nathalie %A Rondeau, Sophie %A Ormieres, Clothide %A Barcia, Giulia %A Tan, Queenie K G %A Thiffault, Isabelle %A Pastinen, Tomi %A Sheikh, Kazim %A Biliciler, Suur %A Mei, Davide %A Melani, Federico %A Shashi, Vandana %A Yaron, Yuval %A Steele, Mary %A Wakeling, Emma %A Østergaard, Elsebet %A Nazaryan-Petersen, Lusine %A Millan, Francisca %A Santiago-Sim, Teresa %A Thevenon, Julien %A Bruel, Ange-Line %A Thauvin-Robinet, Christel %A Popp, Denny %A Platzer, Konrad %A Gawlinski, Pawel %A Wiszniewski, Wojciech %A Marafi, Dana %A Pehlivan, Davut %A Posey, Jennifer E %A Richard A Gibbs %A Gailus-Durner, Valerie %A Guerrini, Renzo %A Fuchs, Helmut %A Hrabě de Angelis, Martin %A Hölter, Sabine M %A Cheung, Hoi-Hung %A Gu, Shen %A Lupski, James R %K Animals %K Cell Line %K Charcot-Marie-Tooth Disease %K DEAD-box RNA Helicases %K Dichlorodiphenyl Dichloroethylene %K DNA Helicases %K Humans %K Mammals %K Mice %K Neoplasm Proteins %K Neurodevelopmental Disorders %X

DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutational constraint of all DDX/DHX paralogs but remains unassociated with disease traits in OMIM. Using exome sequencing and family-based rare-variant analyses, we identified 20 individuals with de novo, ultra-rare, heterozygous missense or loss-of-function (LoF) DHX9 variant alleles. Phenotypes ranged from NDDs to the distal symmetric polyneuropathy axonal Charcot-Marie-Tooth disease (CMT2). Quantitative Human Phenotype Ontology (HPO) analysis demonstrated genotype-phenotype correlations with LoF variants causing mild NDD phenotypes and nuclear localization signal (NLS) missense variants causing severe NDD. We investigated DHX9 variant-associated cellular phenotypes in human cell lines. Whereas wild-type DHX9 was restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from an individual with an NLS variant also showed abnormal cytoplasmic DHX9 accumulation. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Two NDD-associated variants, p.Gly411Glu and p.Arg761Gln, altered DHX9 ATPase activity. The severe NDD-associated variant p.Arg141Gln did not affect DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks. Dhx9 mice exhibited hypoactivity in novel environments, tremor, and sensorineural hearing loss. All together, these results establish DHX9 as a critical regulator of mammalian neurodevelopment and neuronal homeostasis.

%B Am J Hum Genet %V 110 %P 1394-1413 %8 2023 Aug 03 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/37467750?dopt=Abstract %R 10.1016/j.ajhg.2023.06.013 %0 Journal Article %J Cancer Cell %D 2018 %T A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers. %A Berger, Ashton C %A Korkut, Anil %A Kanchi, Rupa S %A Hegde, Apurva M %A Lenoir, Walter %A Liu, Wenbin %A Liu, Yuexin %A Fan, Huihui %A Shen, Hui %A Ravikumar, Visweswaran %A Rao, Arvind %A Schultz, Andre %A Li, Xubin %A Sumazin, Pavel %A Williams, Cecilia %A Mestdagh, Pieter %A Gunaratne, Preethi H %A Yau, Christina %A Bowlby, Reanne %A Robertson, A Gordon %A Tiezzi, Daniel G %A Wang, Chen %A Cherniack, Andrew D %A Godwin, Andrew K %A Kuderer, Nicole M %A Rader, Janet S %A Zuna, Rosemary E %A Sood, Anil K %A Lazar, Alexander J %A Ojesina, Akinyemi I %A Adebamowo, Clement %A Adebamowo, Sally N %A Baggerly, Keith A %A Chen, Ting-Wen %A Chiu, Hua-Sheng %A Lefever, Steve %A Liu, Liang %A MacKenzie, Karen %A Orsulic, Sandra %A Roszik, Jason %A Shelley, Carl Simon %A Song, Qianqian %A Vellano, Christopher P %A Wentzensen, Nicolas %A Weinstein, John N %A Mills, Gordon B %A Levine, Douglas A %A Akbani, Rehan %K Breast Neoplasms %K Databases, Genetic %K DNA Copy Number Variations %K Female %K Gene Expression Profiling %K Gene Expression Regulation, Neoplastic %K Gene Regulatory Networks %K Genetic Predisposition to Disease %K Genital Neoplasms, Female %K Humans %K Mutation %K Organ Specificity %K Prognosis %K Receptors, Estrogen %K RNA, Long Noncoding %X

We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.

%B Cancer Cell %V 33 %P 690-705.e9 %8 2018 Apr 09 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/29622464?dopt=Abstract %R 10.1016/j.ccell.2018.03.014 %0 Journal Article %J Cell Rep %D 2018 %T Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. %A Knijnenburg, Theo A %A Wang, Linghua %A Zimmermann, Michael T %A Chambwe, Nyasha %A Gao, Galen F %A Cherniack, Andrew D %A Fan, Huihui %A Shen, Hui %A Way, Gregory P %A Greene, Casey S %A Liu, Yuexin %A Akbani, Rehan %A Feng, Bin %A Donehower, Lawrence A %A Miller, Chase %A Shen, Yang %A Karimi, Mostafa %A Chen, Haoran %A Kim, Pora %A Jia, Peilin %A Shinbrot, Eve %A Zhang, Shaojun %A Liu, Jianfang %A Hu, Hai %A Bailey, Matthew H %A Yau, Christina %A Wolf, Denise %A Zhao, Zhongming %A Weinstein, John N %A Li, Lei %A Ding, Li %A Mills, Gordon B %A Laird, Peter W %A Wheeler, David A %A Shmulevich, Ilya %A Monnat, Raymond J %A Xiao, Yonghong %A Wang, Chen %K Cell Line, Tumor %K DNA Damage %K Gene Silencing %K Genome, Human %K Humans %K Loss of Heterozygosity %K Machine Learning %K Mutation %K Neoplasms %K Recombinational DNA Repair %K Tumor Suppressor Proteins %X

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.

%B Cell Rep %V 23 %P 239-254.e6 %8 2018 Apr 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29617664?dopt=Abstract %R 10.1016/j.celrep.2018.03.076 %0 Journal Article %J Cell Rep %D 2018 %T Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas. %A Campbell, Joshua D %A Yau, Christina %A Bowlby, Reanne %A Liu, Yuexin %A Brennan, Kevin %A Fan, Huihui %A Taylor, Alison M %A Wang, Chen %A Walter, Vonn %A Akbani, Rehan %A Byers, Lauren Averett %A Creighton, Chad J %A Coarfa, Cristian %A Shih, Juliann %A Cherniack, Andrew D %A Gevaert, Olivier %A Prunello, Marcos %A Shen, Hui %A Anur, Pavana %A Chen, Jianhong %A Cheng, Hui %A Hayes, D Neil %A Bullman, Susan %A Pedamallu, Chandra Sekhar %A Ojesina, Akinyemi I %A Sadeghi, Sara %A Mungall, Karen L %A Robertson, A Gordon %A Benz, Christopher %A Schultz, Andre %A Kanchi, Rupa S %A Gay, Carl M %A Hegde, Apurva %A Diao, Lixia %A Wang, Jing %A Ma, Wencai %A Sumazin, Pavel %A Chiu, Hua-Sheng %A Chen, Ting-Wen %A Gunaratne, Preethi %A Donehower, Larry %A Rader, Janet S %A Zuna, Rosemary %A Al-Ahmadie, Hikmat %A Lazar, Alexander J %A Flores, Elsa R %A Tsai, Kenneth Y %A Zhou, Jane H %A Rustgi, Anil K %A Drill, Esther %A Shen, Ronglei %A Wong, Christopher K %A Stuart, Joshua M %A Laird, Peter W %A Hoadley, Katherine A %A Weinstein, John N %A Peto, Myron %A Pickering, Curtis R %A Chen, Zhong %A Van Waes, Carter %K Carcinoma, Squamous Cell %K Cell Line, Tumor %K DNA Methylation %K Epithelial-Mesenchymal Transition %K Gene Expression Regulation, Neoplastic %K Genomics %K Humans %K Metabolic Networks and Pathways %K Polymorphism, Genetic %X

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

%B Cell Rep %V 23 %P 194-212.e6 %8 2018 Apr 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29617660?dopt=Abstract %R 10.1016/j.celrep.2018.03.063