Medical Specialties Commons^™

A Retrospective Genomic Landscape Of 661 Young Adult Glioblastomas Diagnosed Using 2016 Who Guidelines For Central Nervous System Tumors, James F Haberberger, Worthy Pegram, Nicholas Britt, Kelsie Schiavone, Eric Severson, Radwa Sharaf, Lee A Albacker, Erik Williams, Mirna Lechpammer, Amanda Hemmerich, Douglas Lin, Richard S P Huang, Matthew Hiemenz, Julia Elvin, Ryon Graf, Glenn Lesser, David Kram, Roy Strowd, Wenya Linda Bi, Lori A Ramkissoon, Michael B Cohen, Prasanth Reddy, James Creeden, Jeffrey S Ross, Brian M Alexander, Shakti H Ramkissoon

Faculty, Staff and Student Publications

The authors present a cohort of 661 young adult glioblastomas diagnosed using 2016 WHO World Health Organization Classification of Tumors of the Central Nervous System, utilizing comprehensive genomic profiling (CGP) to explore their genomic landscape and assess their relationship to currently defined disease entities. This analysis explored variants with evidence of pathogenic function, common copy number variants (CNVs), and several novel fusion events not described in literature. Tumor mutational burden (TMB) mutational signatures, anatomic location, and tumor recurrence are further explored. Using data collected from CGP, unsupervised machine-learning techniques were leveraged to identify 10 genomic classes in previously assigned young …

An Evolutionary Perspective On Complex Neuropsychiatric Disease, Jon M Mcclellan, Anthony W Zoghbi, Joseph D Buxbaum, Carolina Cappi, James J Crowley, Jonathan Flint, Dorothy E Grice, Suleyman Gulsuner, Conrad Iyegbe, Sanjeev Jain, Po-Hsiu Kuo, Maria Claudia Lattig, Maria Rita Passos-Bueno, Meera Purushottam, Dan J Stein, Anna B Sunshine, Ezra S Susser, Christopher A Walsh, Olivia Wootton, Mary-Claire King

Faculty, Staff and Students Publications

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields …

Feasible Diet And Circadian Interventions Reduce In Vivo Progression Of Flt3-Itd-Positive Acute Myeloid Leukemia, Megan Rodriguez, Baharan Fekry, Brianna Murphy, Mary Figueroa, Tiewei Cheng, Margaret Raber, Lisa Wartenberg, Donna Bell, Lisa Triche, Karla Crawford, Huaxian Ma, Kendra Allton, Ruwaida Ahmed, Jaime Tran, Christine Ranieri, Marina Konopleva, Michelle Barton, Cesar Nunez, Kristin Eckel-Mahan, Joya Chandra

Faculty, Staff and Student Publications

BACKGROUND: Acute myeloid leukemia (AML) with an internal tandem duplication in the fms-like tyrosine kinase receptor 3 gene (FLT3-ITD) is associated with poor survival, and few studies have examined the impact of modifiable behaviors, such as nutrient quality and timing, in this subset of acute leukemia.

METHODS: The influence of diet composition (low-sucrose and/or low-fat diets) and timing of diet were tested in tandem with anthracycline treatment in orthotopic xenograft mouse models. A pilot clinical study to test receptivity of pediatric leukemia patients to macronutrient matched foods was conducted. A role for the circadian protein, BMAL1 (brain and muscle ARNT-like …

Sotorasib With Panitumumab In Chemotherapy-Refractory Kras G12c-Mutated Colorectal Cancer: A Phase 1b Trial, Yasutoshi Kuboki, Marwan Fakih, John Strickler, Rona Yaeger, Toshiki Masuishi, Edward J Kim, Christine M Bestvina, Scott Kopetz, Gerald S Falchook, Corey Langer, John Krauss, Sonam Puri, Panli Cardona, Emily Chan, Tracy Varrieur, Lata Mukundan, Abraham Anderson, Qui Tran, David S Hong

Faculty, Staff and Student Publications

The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRAS

Phospholipid Metabolic Adaptation Promotes Survival Of Idh2 Mutant Acute Myeloid Leukemia Cells, Tatsuya Morishima, Koichi Takahashi, Desmond Wai Loon Chin, Yuxin Wang, Kenji Tokunaga, Yuichiro Arima, Masao Matsuoka, Toshio Suda, Hitoshi Takizawa

Faculty, Staff and Student Publications

Genetic mutations in the isocitrate dehydrogenase (IDH) gene that result in a pathological enzymatic activity to produce oncometabolite have been detected in acute myeloid leukemia (AML) patients. While specific inhibitors that target mutant IDH enzymes and normalize intracellular oncometabolite level have been developed, refractoriness and resistance has been reported. Since acquisition of pathological enzymatic activity is accompanied by the abrogation of the crucial WT IDH enzymatic activity in IDH mutant cells, aberrant metabolism in IDH mutant cells can potentially persist even after the normalization of intracellular oncometabolite level. Comparisons of isogenic AML cell lines with and without IDH2 gene mutations …

Dysregulation Of Epigenetic Modifications In Inborn Errors Of Immunity, Zhongyao Xiao, Rongjing He, Zihan Zhao, Taiping Chen, Zhengzhou Ying

Faculty, Staff and Student Publications

Inborn errors of immunity (IEIs) are a group of typically monogenic disorders characterized by dysfunction in the immune system. Individuals with these disorders experience increased susceptibility to infections, autoimmunity and malignancies due to abnormal immune responses. Epigenetic modifications, including DNA methylation, histone modifications and chromatin remodeling, have been well explored in the regulation of immune cell development and effector function. Aberrant epigenetic modifications can disrupt gene expression profiles crucial for immune responses, resulting in impaired immune cell differentiation and function. Dysregulation of these processes caused by mutations in genes involving in epigenetic modifications has been associated with various IEIs. In …

Systemic Complications Of Aicardi Goutières Syndrome Using Real-World Data, Isabella Peixoto De Barcelos, Amanda K Jan, Nicholson Modesti, Sarah Woidill, Francesco Gavazzi, David Isaacs, Russell D'Aiello, Anjana Sevagamoorthy, Lauren Charlton, Amy Pizzino, Johanna Schmidt, Keith Van Haren, Stephanie Keller, Florian Eichler, Lisa T Emrick, Jamie L Fraser, Justine Shults, Adeline Vanderver, Laura A Adang

Faculty, Staff and Students Publications

Objective: Aicardi Goutières Syndrome (AGS) is a rare genetic interferonopathy associated with diverse multisystemic complications. A critical gap exists in our understanding of its longitudinal, systemic disease burden, complicated by delayed diagnosis. To address this need, real-world data extracted from existing medical records were used to characterize the longitudinal disease burden.

Methods: All subjects (n = 167) with genetically confirmed AGS enrolled in the Myelin Disorders Biorepository Project (MDBP) were included. As available in medical records, information was collected on subject demographics, age of onset, and disease complications. Information from published cases of AGS (2007-2022; n = 129) with individual-level …

Molecular Profiling Of A Hepatocellular Neoplasm Not Otherwise Specified (Hcn-Nos) Demonstrates Distinct Molecular Features In Hepatoblastoma And Hcc-Like Components, Yan Chen Wongworawat, Stephen F Sarabia, Martin Urbicain, Paola Francalanci, Pavel Sumazin, Rita Alaggio, Dolores H López-Terrada

Faculty, Staff and Students Publications

Hepatoblastomas (HB) are embryonal tumors with quiet genomes diagnosed mostly in children under 3 years of age and often cured by surgical resection and chemotherapy. However, a subset of HBs behave aggressively, displaying characteristic histologic features and higher genomic instability. Hepatocellular neoplasm-not otherwise specified (HCN-NOS) is a provisional diagnostic category for tumors exhibiting either intermediate or a combination of both HB and hepatocellular carcinoma (HCC) histological features. In this study, we characterized an HCN-NOS diagnosed in a 3-year-old patient presenting with a liver mass, in which both HB and HCC histological components were amendable to macro-dissection and molecular profiling. The …

Diminished Tmem100 Expression In A Newborn With Acinar Dysplasia And A Novel Tbx4 Variant: A Case Report, Przemyslaw Szafranski, Silvia Patrizi, Tomasz Gambin, Bushra Afzal, Emily Schlotterbeck, Justyna A Karolak, Gail Deutsch, Drucilla Roberts, Paweł Stankiewicz

Faculty, Staff and Students Publications

Acinar dysplasia (AcDys) of the lung is a rare lethal developmental disorder in neonates characterized by severe respiratory failure and pulmonary arterial hypertension refractory to treatment. Recently, abnormalities of TBX4-FGF10-FGFR2-TMEM100 signaling regulating lung development have been reported in patients with AcDys due to heterozygous single-nucleotide variants (SNVs) or copy-number variant (CNV) deletions involving TBX4, FGF10, or FGFR2. Here, we describe a female neonate who died at 4 hours of life due to severe respiratory distress related to AcDys diagnosed by postmortem histopathologic evaluation. Genomic analyses revealed a novel deleterious heterozygous missense variant c.728A>C (p.Asn243Thr) in TBX4 that arose …

Dna Mismatch Repair Defect And Intratumor Heterogeneous Deficiency Differently Impact Immune Responses In Diffuse Large B-Cell Lymphoma, Zijun Y Xu-Monette, Cancan Luo, Li Yu, Yong Li, Govind Bhagat, Alexandar Tzankov, Carlo Visco, Xiangshan Fan, Karen Dybkaer, Ali Sakhdari, Nicholas T Wang, Alyssa F Yuan, April Chiu, Wayne Tam, Youli Zu, Eric D Hsi, Anamarija M Perry, Wenting Song, Dennis O'Malley, Qingyan Au, Harry Nunns, Heounjeong Go, Michael B Møller, Benjamin M Parsons, Santiago Montes-Moreno, Maurilio Ponzoni, Andrés J M Ferreri, Aliyah R Sohani, Jeremy S Abramson, Bing Xu, Ken H Young

Faculty, Staff and Students Publications

Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression …

Novel, Pathogenic Insertion Variant Of Gsdme Associates With Autosomal Dominant Hearing Loss In A Large Chinese Pedigree, Jingliang Cheng, Ting Li, Qi Tan, Jiewen Fu, Lianmei Zhang, Luquan Yang, Baixu Zhou, Lisha Yang, Shangyi Fu, Alora Grace Linehan, Junjiang Fu

Children’s Nutrition Research Center Staff Publications

Nonsyndromic hearing loss (NSHL) is a genetically diverse, highly heterogeneous condition characterised by deafness, and Gasdermin E (GSDME) variants have been identified as directly inducing autosomal dominant NSHL. While many NSHL cases associated with GSDME involve the skipping of exon 8, there is another, less understood pathogenic insertion variant specifically found in Chinese pedigrees that causes deafness, known as autosomal dominant 5 (DFNA5) hearing loss. In this study, we recruited a large Chinese pedigree, conducted whole‐exome and Sanger sequencing to serve as a comprehensive clinical examination, and extracted genomic DNA samples for co‐segregation analysis of the members. Conservation …

Fgf5, Evelyn A Carrion, Malcolm M Moses, Richard R Behringer

Faculty, Staff and Student Publications

FGF5 functions as a negative regulator of the hair cycle in mammals. It is expressed in the outer root sheath of hair follicles during the late anagen phase of the hair cycle. It functions as a signaling molecule, mediating the transition of the anagen growth phase to catagen regression phase of the hair cycle. Spontaneous and engineered FGF5 mutations in mammalian animal models result in long hair phenotypes. In humans, inherited FGF5 mutations result in trichomegaly (long eyelashes). Knockdown of fgf5 in zebrafish embryos results in inner ear alterations. Alterations in FGF5 expression are also associated with various human pathologies.

Circulating Tumor Dna (Ctdna) As A Biomarker Of Response To Therapy In Advanced Hepatocellular Carcinoma Treated With Nivolumab, Yehia I Mohamed, Sunyoung S Lee, Tarik Demir, Shadi Chamseddine, Zishuo Ian Hu, Lianchun Xiao, Khaled Elsayes, Jeffrey S Morris, Robert A Wolff, Rikita Hiatia, Aliya Qayyum, Asif Rashid, Dan G Duda, James C Yao, Michael Lapelusa, Eugene J Koay, Armeen Mahvash, Ahmed Al Azzam, Ecaterina E Dumbrava, Manal Hassan, Hesham M Amin, Ahmed Omar Kaseb

Faculty, Staff and Student Publications

Background: Circulating tumor DNA (ctDNA) is a promising non-invasive marker for detection, diagnosis, treatment selection, and prognosis of hepatocellular carcinoma (HCC).

Objective: This study aimed to examine the utility of ctDNA as a prognostic and predictive tool in HCC patients treated with nivolumab.

Methods: We analyzed pre-treatment ctDNA from 44 HCC patients using comprehensive genomic testing on a commercially available platform. We utilized log rank test and univariate Cox models to correlate overall survival (OS) and progression-free survival (PFS) with ctDNA expressions.

Results: Of 44 patients, 77.3% were men with median age of 67 years. All but 3 patients had …

Rapid Detection Of Mutations In Csf-Cftna With The Genexus Integrated Sequencer, Srividya Arjuna, Mauli Shah, Antonio Dono, Luis Nunez-Rubiano, Pavel S Pichardo-Rojas, Jay-Jiguang Zhu, Roy F Riascos, Rajyalakshmi Luthra, Sinchita Roy-Chowdhuri, Dzifa Duose, Daniel H Wang, Frederick F Lang, Yoshua Esquenazi, Leomar Y Ballester

Faculty, Staff and Student Publications

PURPOSE: Genomic alterations are fundamental for molecular-guided therapy in patients with breast and lung cancer. However, the turn-around time of standard next-generation sequencing assays is a limiting factor in the timely delivery of genomic information for clinical decision-making.

METHODS: In this study, we evaluated genomic alterations in 54 cerebrospinal fluid samples from 33 patients with metastatic lung cancer and metastatic breast cancer to the brain using the Oncomine Precision Assay on the Genexus sequencer. There were nine patients with samples collected at multiple time points.

RESULTS: Cell-free total nucleic acids (cfTNA) were extracted from CSF (0.1-11.2 ng/μl). Median base coverage …

Belzutifan, Hif-2Α Inhibitor, And Clear Cell Renal Cell Carcinoma With Somatic Von-Hippel-Lindau Loss-Of-Function Mutation, Kok Hoe Chan, Ningjing Li, Ran Lador, Mark Amsbaugh, Anneliese Gonzalez, Putao Cen

Faculty, Staff and Student Publications

The Von-Hippel-Lindau (VHL) gene, acting as a tumor suppressor, plays a crucial role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Approximately 90% of individuals with advanced ccRCC exhibit somatic mutations in the VHL gene. Belzutifan, orally administered small-molecule inhibitor of hypoxia-induced factor-2α, has demonstrated promising efficacy in solid tumors associated with germline loss-of-function mutations in VHL, including ccRCC. However, its impact on cases with somatic or sporadic VHL mutations remains unclear. Here, we present 2 cases where belzutifan monotherapy was employed in patients with advanced ccRCC and somatic loss-of-function mutations in VHL. Both patients exhibited a swift …

P53r245w Mutation Fuels Cancer Initiation And Metastases In Nash-Driven Liver Tumorigenesis, Denada Dibra, Mihai Gagea, Yuan Qi, Gilda P Chau, Xiaoping Su, Guillermina Lozano

Faculty, Staff and Student Publications

Obesity is a significant global health concern. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are common risk factors for hepatocellular carcinoma (HCC) and are closely associated with metabolic comorbidities, including obesity and diabetes. The TP53 tumor suppressor is the most frequently mutated gene in liver cancers, with half of these alterations being missense mutations. These mutations produce highly abundant proteins in cancer cells which have both inhibitory effects on wildtype (WT) p53, and gain-of-function (GOF) activities that contribute to tumor progression. A Western diet increases p53 activity in the liver. To elucidate the functional consequences of Trp53 mutations in …

Targeted Therapeutic Strategies For Melanoma, Shiwei Zhang, Ruxin Xie, Ai Zhong, Junjie Chen

Faculty, Staff and Student Publications

Melanoma accounts for a small proportion of skin cancers diagnosed each year, but it has a high degree of malignancy and rapid progression, resulting in a short survival period for patients. The incidence of melanoma continues to rise, and now melanoma accounts for 1.7% of cancer diagnoses worldwide and is the fifth most common cancer in the United States. With the development of high-throughput sequencing technologies, the understanding of the pathophysiology of melanoma had also been improved. The most common activating mutations in melanoma cells are BRAF , NRAS , and KIT mutations, which disrupt cell signaling pathways related to …

Allelic Strengths Of Encephalopathy-Associated Uba5 Variants Correlate Between In Vivo And In Vitro Assays, Xueyang Pan, Albert N Alvarez, Mengqi Ma, Shenzhao Lu, Michael W Crawford, Lauren C Briere, Oguz Kanca, Shinya Yamamoto, David A Sweetser, Jenny L Wilson, Ruth J Napier, Jonathan N Pruneda, Hugo J Bellen

Faculty, Staff and Students Publications

Protein UFMylation downstream of the E1 enzyme UBA5 plays essential roles in development and endoplasmic reticulum stress. Variants in the UBA5 gene are associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder characterized by early-onset encephalopathy, movement abnormalities, global developmental delay, intellectual disability, and seizures. DEE44 is caused by at least 12 different missense variants described as loss of function (LoF), but the relationships between genotypes and molecular or clinical phenotypes remain to be established. We developed a humanized UBA5 fly model and biochemical activity assays in order to describe in vivo and in vitro genotype–phenotype relationships …

Novel Sox10 Indel Mutations Drive Schwannomas Through Impaired Transactivation Of Myelination Gene Programs, Erik A Williams, Ajay Ravindranathan, Rohit Gupta, Nicholas O Stevers, Abigail K Suwala, Chibo Hong, Somang Kim, Jimmy Bo Yuan, Jasper Wu, Jairo Barreto, Calixto-Hope G Lucas, Emily Chan, Melike Pekmezci, Philip E Leboit, Thaddeus Mully, Arie Perry, Andrew Bollen, Jessica Van Ziffle, W Patrick Devine, Alyssa T Reddy, Nalin Gupta, Kristen M Basnet, Robert J B Macaulay, Patrick Malafronte, Han Lee, William H Yong, Kevin Jon Williams, Tareq A Juratli, Douglas A Mata, Richard S P Huang, Matthew C Hiemenz, Dean C Pavlick, Garrett M Frampton, Tyler Janovitz, Jeffrey S Ross, Susan M Chang, Mitchel S Berger, Line Jacques, Jun S Song, Joseph F Costello, David A Solomon

Faculty, Staff and Student Publications

BACKGROUND: Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.

METHODS: We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a …

Rab1a Haploinsufficiency Phenocopies The 2p14-P15 Microdeletion And Is Associated With Impaired Neuronal Differentiation, Jonathan J Rios, Yang Li, Nandina Paria, Ryan J Bohlender, Chad Huff, Jill A Rosenfeld, Pengfei Liu, Weimin Bi, Kentaro Haga, Mitsunori Fukuda, Shayal Vashisth, Kiran Kaur, Maria H Chahrour, Michael B Bober, Angela L Duker, Farah A Ladha, Neil A Hanchard, Kristhen Atala, Anas M Khanshour, Linsley Smith, Carol A Wise, Mauricio R Delgado

Faculty, Staff and Student Publications

Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense mutation (c.523C>T [p.Arg175Ter]) in the highly conserved RAB1A. The mutation is predicted to produce a truncated protein with an intact RAB GTPase domain but without two C-terminal cysteine residues required for proper subcellular protein localization. Additional RAB1A mutations, including two frameshift mutations and …

Degronmd: Leveraging Evolutionary And Structural Features For Deciphering Protein-Targeted Degradation, Mutations, And Drug Response To Degrons, Haodong Xu, Ruifeng Hu, Zhongming Zhao

Faculty, Staff and Student Publications

Protein-targeted degradation is an emerging and promising therapeutic approach. The specificity of degradation and the maintenance of cellular homeostasis are determined by the interactions between E3 ubiquitin ligase and degradation signals, known as degrons. The human genome encodes over 600 E3 ligases; however, only a small number of targeted degron instances have been identified so far. In this study, we introduced DegronMD, an open knowledgebase designed for the investigation of degrons, their associated dysfunctional events, and drug responses. We revealed that degrons are evolutionarily conserved and tend to occur near the sites of protein translational modifications, particularly in the regions …

Precision Therapy For A Medically Actionable Atp1a3 Variant From A Genomic Medicine Program In An Underserved Population, Cara P Ford, Rebecca O Littlejohn, Ryan German, Blake Vuocolo, Jose Aceves, Liesbeth Vossaert, Nichole Owen, Michael Wangler, Carrie A Schmid

Duncan NRI Faculty and Staff Publications

Background: Genomic medicine is revolutionizing the diagnosis of rare diseases, but the implementation has not benefited underrepresented populations to the same degree. Here, we report the case of a 7-year-old boy with hypotonia, global developmental delay, strabismus, seizures, and previously suspected mitochondrial myopathy. This proband comes from an underrepresented minority and was denied exome sequencing by his public insurance.

Methods: After informed consent was obtained, buccal cells from the proband were collected and whole exome sequencing was performed. Illumina Dragen and Emedgene software was used to analyze the data at Baylor Genetics. The variants were further intepreted according to ACMG …

Atm Mutations Associate With Distinct Co-Mutational Patterns And Therapeutic Vulnerabilities In Nsclc, Natalie I Vokes, Ana Galan Cobo, Margarita Fernandez-Chas, David Molkentine, Santiago Treviño, Vitaly Druker, Yu Qian, Sonia Patel, Stephanie Schmidt, Lingzhi Hong, Jeff Lewis, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, J Jack Lee, Marcelo V Negrao, Don L Gibbons, Ara Vaporciyan, Xiuning Le, Jia Wu, Jianjun Zhang, Una Rigney, Sonia Iyer, Emma Dean, John V Heymach

Faculty, Staff and Student Publications

PURPOSE: Ataxia-telangiectasia mutated (ATM) is the most frequently mutated DNA damage repair gene in non-small cell lung cancer (NSCLC). However, the molecular correlates of ATM mutations and their clinical implications have not been fully elucidated.

EXPERIMENTAL DESIGN: Clinicopathologic and genomic data from 26,587 patients with NSCLC from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in ATM-mutant tumors. We used the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of …

Acute Myeloid Leukemia With Mutated Tp53: Is This Newly Proposed Entity Oversimplifying A Complex Group Of Neoplasms?, Hong Fang, L Jeffery Medeiros, Wei Wang

Faculty, Staff and Student Publications

No abstract provided.

Enhanced Cd19 Activity In B Cells Contributes To Immunodeficiency In Mice Deficient In The Icf Syndrome Gene Zbtb24, Zhengzhou Ying, Swanand Hardikar, Joshua B Plummer, Tewfik Hamidi, Bin Liu, Yueping Chen, Jianjun Shen, Yunxiang Mu, Kevin M Mcbride, Taiping Chen

Faculty, Staff and Student Publications

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations in DNMT3B, ZBTB24, CDCA7, or HELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here, we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels …

Clinico-Genomic Profiling Of Conventional And Dedifferentiated Chondrosarcomas Reveals Tp53 Mutation To Be Associated With Worse Outcomes, Ryan A Denu, Richard K Yang, Alexander J Lazar, Shalin S Patel, Valerae O Lewis, Jason Roszik, J Andrew Livingston, Wei-Lien Wang, Kenna R Shaw, Ravin Ratan, Maria A Zarzour, Justin Bird, Shaan Raza, Kadir C Akdemir, Jordi Rodon Ahnert, Vivek Subbiah, Shreyaskumar Patel, Anthony P Conley

Faculty, Staff and Student Publications

PURPOSE: Chondrosarcomas are the most common primary bone tumor in adults. Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are prevalent. We aimed to assess the clinico-genomic properties of IDH mutant versus IDH wild-type (WT) chondrosarcomas as well as alterations in other genes.

EXPERIMENTAL DESIGN: We included 93 patients with conventional and dedifferentiated chondrosarcoma for which there were available clinical next-generation sequencing data. Clinical and genomic data were extracted and compared between IDH mutant and IDH WT chondrosarcomas and between TP53 mutant and TP53 WT chondrosarcomas.

RESULTS: IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more common in chondrosarcomas arising …

Kinome Profiling Identifies Mark3 And Stk10 As Potential Therapeutic Targets In Uveal Melanoma, Usman Baqai, Alison M Kurimchak, Isabella V Trachtenberg, Timothy J Purwin, Jelan I Haj, Anna Han, Kristine Luo, Nikole Fandino Pachon, Angela Jeon, Vivian Chua, Michael A Davies, J Silvio Gutkind, Jeffrey L Benovic, James S Duncan, Andrew E Aplin

Faculty, Staff and Student Publications

Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the "dark kinome". Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. …

The Landscape Of Alterations From 1407 Ultra-Rare Sarcomas From The Aacr Genie Database: Clinical Implications, Ryan A Denu, Justin T Moyers, Mohamed A Gouda, Anthony P Conley, Alexander J Lazar, Vivek Subbiah

Faculty, Staff and Student Publications

Purpose: Ultra-rare sarcomas (URS) comprise a group of orphan diseases with an incidence of ≤1/1,000,000 people per year. We aimed to assess clinically actionable genomic alterations in URS.

Experimental design: Data were extracted from the GENIE database using cBioPortal. OncoKB was used to assess for clinical actionability of mutations. Tumor mutational burden (TMB) was inferred from clinical sequencing data.

Results: Soft tissue (ST) URS made up 23.5% of ST sarcoma cases, and bone URS made up 16.5% of bone sarcoma cases. The most commonly mutated gene in all four groups was TP53. The most common fusions involved EWSR1. The most …

Cigarette Smoke Exposure Accelerates Aml Progression In Flt3-Itd Models, Mary Figueroa, Huaxian Ma, Mansour Alfayez, Daniel Enrique Morales-Mantilla, Fei Wang, Yue Lu, Marcos R Estecio, Katherine Y King, Eugenie Kleinerman, Seyed Javad Moghaddam, Naval Daver, Michael Andreeff, Marina Konopleva, Courtney Dinardo, Joya Chandra

Faculty, Staff and Student Publications

No abstract provided.

Single-Cell Analysis Differentiates The Effects Of P53 Mutation And P53 Loss On Cell Compositions Of Oncogenic Kras-Driven Pancreatic Cancer, Xinlei Sun, Daowei Yang, Yang Chen

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignant disease with a dismal prognosis. In the past decades, a plethora of genetically engineered mouse models (GEMMs) with autochthonous pancreatic tumor development have greatly facilitated studies of pancreatic cancer. Commonly used GEMMs of PDAC often harbor the oncogenic KRAS driver mutation (KrasG12D), in combination with either p53 mutation by knock-in strategy (Trp53R172H) or p53 loss by conditional knockout (Trp53cKO) strategy, in pancreatic cell lineages. However, the systematic comparison of the tumor microenvironment between KrasG12D; Trp53R172H (KPmut) mouse models and KrasG12D; Trp53cKO (KPloss) mouse models …