Medical Genetics Commons^™

Imaging Characteristics Of 4th Ventricle Subependymoma, Ali S Haider, Tarek Y El Ahmadieh, Maryam Haider, Kimmo J Hatanpaa, Marco C Pinho, Bruce E Mickey, Raymond Sawaya, Gregory N Fuller, Donald F Schomer, Maria Gule-Monroe

Faculty, Staff and Student Publications

Purpose: Subependymomas located within the 4th ventricle are rare, and the literature describing imaging characteristics is sparse. Here, we describe the clinical and radiological characteristics of 29 patients with 4th ventricle subependymoma.

Methods: This is a retrospective multi-center study performed after Institutional Review Board (IRB) approval. Patients diagnosed with suspected 4th ventricle subependymoma were identified. A review of clinical, radiology, and pathology reports along with magnetic resonance imaging (MRI) images was performed.

Results: Twenty-nine patients, including 6 females, were identified. Eighteen patients underwent surgery with histopathological confirmation of subependymoma. The median age at diagnosis was 52 years. Median tumor volume …

Auto-Detection And Segmentation Of Involved Lymph Nodes In Hpv-Associated Oropharyngeal Cancer Using A Convolutional Deep Learning Neural Network, Nicolette Taku, Kareem A Wahid, Lisanne V Van Dijk, Jaakko Sahlsten, Joel Jaskari, Kimmo Kaski, Clifton D Fuller, Mohamed A Naser

Faculty, Staff and Student Publications

PURPOSE: Segmentation of involved lymph nodes on head and neck computed tomography (HN-CT) scans is necessary for the radiotherapy planning of early-stage human papilloma virus (HPV) associated oropharynx cancers (OPC). We aimed to train a deep learning convolutional neural network (DL-CNN) to segment involved lymph nodes on HN-CT scans.

METHODS: Ground-truth segmentation of involved nodes was performed on pre-surgical HN-CT scans for 90 patients who underwent levels II-IV neck dissection for node-positive HPV-OPC (training/validation [n = 70] and testing [n = 20]). A 5-fold cross validation approach was used to train 5 DL-CNN sub-models based on a residual U-net architecture. …

Swallowing After Primary Tors And Unilateral Or Bilateral Radiation For Low- To Intermediate-Risk Tonsil Cancer, Carly E A Barbon, Christopher M K Yao, Christine B Peterson, Amy C Moreno, Ryan P Goepfert, Faye M Johnson, Gregory M Chronowski, Clifton D Fuller, Neil D Gross, Katherine A Hutcheson

Faculty, Staff and Student Publications

Objective: The primary course of treatment for patients with low- to intermediate-risk tonsil cancer has evolved with a shift toward primary transoral robotic surgery (TORS) or radiation therapy (RT). While favorable outcomes have been reported after deintensification via unilateral TORS or RT (uniRT), comparisons of functional outcomes between these treatments are lacking. We compared clinical outcomes (Dynamic Imaging Grade of Swallowing Toxicity [DIGEST] and feeding tube [FT]) and patient-reported swallowing outcomes (MD Anderson Dysphagia Inventory [MDADI]) based on primary treatment strategy: TORS, uniRT, or bilateral RT (biRT).

Study design: Secondary analysis of prospective cohort.

Setting: Single institution.

Methods: The study …

Spatially Restricted Drivers And Transitional Cell Populations Cooperate With The Microenvironment In Untreated And Chemo-Resistant Pancreatic Cancer, Daniel Cui Zhou, Reyka G Jayasinghe, Siqi Chen, John M Herndon, Michael D Iglesia, Pooja Navale, Michael C Wendl, Wagma Caravan, Kazuhito Sato, Erik Storrs, Chia-Kuei Mo, Jingxian Liu, Austin N Southard-Smith, Yige Wu, Nataly Naser Al Deen, John M Baer, Robert S Fulton, Matthew A Wyczalkowski, Ruiyang Liu, Catrina C Fronick, Lucinda A Fulton, Andrew Shinkle, Lisa Thammavong, Houxiang Zhu, Hua Sun, Liang-Bo Wang, Yize Li, Chong Zuo, Joshua F Mcmichael, Sherri R Davies, Elizabeth L Appelbaum, Keenan J Robbins, Sara E Chasnoff, Xiaolu Yang, Ashley N Reeb, Clara Oh, Mamatha Serasanambati, Preet Lal, Rajees Varghese, Jay R Mashl, Jennifer Ponce, Nadezhda V Terekhanova, Lijun Yao, Fang Wang, Lijun Chen, Michael Schnaubelt, Rita Jui-Hsien Lu, Julie K Schwarz, Sidharth V Puram, Albert H Kim, Sheng-Kwei Song, Kooresh I Shoghi, Ken S Lau, Tao Ju, Ken Chen, Deyali Chatterjee, William G Hawkins, Hui Zhang, Samuel Achilefu, Milan G Chheda, Stephen T Oh, William E Gillanders, Feng Chen, David G Denardo, Ryan C Fields, Li Ding

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells …

Hic2 Controls Developmental Hemoglobin Switching By Repressing Bcl11a Transcription, Peng Huang, Scott A Peslak, Ren Ren, Eugene Khandros, Kunhua Qin, Cheryl A Keller, Belinda Giardine, Henry W Bell, Xianjiang Lan, Malini Sharma, John R Horton, Osheiza Abdulmalik, Stella T Chou, Junwei Shi, Merlin Crossley, Ross C Hardison, Xiaodong Cheng, Gerd A Blobel

Faculty, Staff and Student Publications

The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin (HBG) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of BCL11A transcription. HIC2 and BCL11A are reciprocally expressed during development. Forced expression of HIC2 in adult erythroid cells inhibits BCL11A transcription and induces HBG expression. HIC2 binds to erythroid BCL11A enhancers to reduce chromatin accessibility and binding of transcription factor GATA1, …

Repurposing Epigenetic Inhibitors To Target The Clostridioides Difficile-Specific Dna Adenine Methyltransferase And Sporulation Regulator Cama, Jujun Zhou, John R Horton, Dan Yu, Ren Ren, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

Epigenetically targeted therapeutic development, particularly for SAM-dependent methylations of DNA, mRNA and histones has been proceeding rapidly for cancer treatments over the past few years. However, this approach has barely begun to be exploited for developing new antibiotics, despite an overwhelming global need to counter antimicrobial resistance. Here, we explore whether SAM analogues, some of which are in (pre)clinical studies as inhibitors of human epigenetic enzymes, can also inhibit Clostridioides difficile-specific DNA adenine methyltransferase (CamA), a sporulation regulator present in all C. difficile genomes sequenced to date, but found in almost no other bacteria. We found that SGC0946 (an …

Tumor Immune Contexture Is A Determinant Of Anti-Cd19 Car T Cell Efficacy In Large B Cell Lymphoma, Nathalie Scholler, Regis Perbost, Frederick L Locke, Michael D Jain, Sarah Turcan, Corinne Danan, Edmund C Chang, Sattva S Neelapu, David B Miklos, Caron A Jacobson, Lazaros J Lekakis, Yi Lin, Armin Ghobadi, Jenny J Kim, Justin Chou, Vicki Plaks, Zixing Wang, Allen Xue, Mike Mattie, John M Rossi, Adrian Bot, Jérôme Galon

Faculty, Staff and Student Publications

Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell …

Clinical Acceptability Of Fully Automated External Beam Radiotherapy For Cervical Cancer With Three Different Beam Delivery Techniques, Dong Joo Rhee, Anuja Jhingran, Kai Huang, Tucker J Netherton, Nazia Fakie, Ingrid White, Alicia Sherriff, Carlos E Cardenas, Lifei Zhang, Surendra Prajapati, Stephen F Kry, Beth M Beadle, William Shaw, Frederika O'Reilly, Jeannette Parkes, Hester Burger, Chris Trauernicht, Hannah Simonds, Laurence E Court

Faculty, Staff and Student Publications

Purpose: To fully automate CT-based cervical cancer radiotherapy by automating contouring and planning for three different treatment techniques.

Methods: We automated three different radiotherapy planning techniques for locally advanced cervical cancer: 2D 4-field-box (4-field-box), 3D conformal radiotherapy (3D-CRT), and volumetric modulated arc therapy (VMAT). These auto-planning algorithms were combined with a previously developed auto-contouring system. To improve the quality of the 4-field-box and 3D-CRT plans, we used an in-house, field-in-field (FIF) automation program. Thirty-five plans were generated for each technique on CT scans from multiple institutions and evaluated by five experienced radiation oncologists from three different countries. Every plan was …

Development And Validation Of A Checklist For Use With Automatically Generated Radiotherapy Plans, Kelly A Nealon, Laurence E Court, Raphael J Douglas, Lifei Zhang, Eun Young Han

Faculty, Staff and Student Publications

Purpose: To develop a checklist that improves the rate of error detection during the plan review of automatically generated radiotherapy plans.

Methods: A custom checklist was developed using guidance from American Association of Physicists in Medicine task groups 275 and 315 and the results of a failure modes and effects analysis of the Radiation Planning Assistant (RPA), an automated contouring and treatment planning tool. The preliminary checklist contained 90 review items for each automatically generated plan. In the first study, eight physicists were recruited from our institution who were familiar with the RPA. Each physicist reviewed 10 artificial intelligence-generated resident …

Integrated Imaging And Molecular Analysis To Decipher Tumor Microenvironment In The Era Of Immunotherapy, Jia Wu, Aaron T Mayer, Ruijiang Li

Faculty, Staff and Student Publications

Radiological imaging is an integral component of cancer care, including diagnosis, staging, and treatment response monitoring. It contains rich information about tumor phenotypes that are governed not only by cancer cellintrinsic biological processes but also by the tumor microenvironment, such as the composition and function of tumor-infiltrating immune cells. By analyzing the radiological scans using a quantitative radiomics approach, robust relations between specific imaging and molecular phenotypes can be established. Indeed, a number of studies have demonstrated the feasibility of radiogenomics for predicting intrinsic molecular subtypes and gene expression signatures in breast cancer based on MRI. In parallel, promising results …

Genetic Loci And Prioritization Of Genes For Kidney Function Decline Derived From A Meta-Analysis Of 62 Longitudinal Genome-Wide Association Studies, Mathias Gorski, Humaira Rasheed, Alexander Teumer, Laurent F Thomas, Sarah E Graham, Gardar Sveinbjornsson, Thomas W Winkler, Felix Günther, Klaus J Stark, Jin-Fang Chai, Bamidele O Tayo, Matthias Wuttke, Yong Li, Adrienne Tin, Tarunveer S Ahluwalia, Johan Ärnlöv, Bjørn Olav Åsvold, Stephan J L Bakker, Bernhard Banas, Nisha Bansal, Mary L Biggs, Ginevra Biino, Michael Böhnke, Eric Boerwinkle, Erwin P Bottinger, Hermann Brenner, Ben Brumpton, Robert J Carroll, Layal Chaker, John Chalmers, Miao-Li Chee, Miao-Ling Chee, Ching-Yu Cheng, Audrey Y Chu, Marina Ciullo, Massimiliano Cocca, James P Cook, Josef Coresh, Daniele Cusi, Martin H De Borst, Frauke Degenhardt, Kai-Uwe Eckardt, Karlhans Endlich, Michele K Evans, Mary F Feitosa, Andre Franke, Sandra Freitag-Wolf, Christian Fuchsberger, Piyush Gampawar, Ron T Gansevoort, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Christian Gieger, Daniel F Gudbjartsson, Stein Hallan, Pavel Hamet, Asahi Hishida, Kevin Ho, Edith Hofer, Bernd Holleczek, Hilma Holm, Anselm Hoppmann, Katrin Horn, Nina Hutri-Kähönen, Kristian Hveem, Shih-Jen Hwang, M Arfan Ikram, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Irma Karabegović, Chiea-Chuen Khor, Wolfgang Koenig, Holly Kramer, Bernhard K Krämer, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Leslie A Lange, Terho Lehtimäki, Man Li, Wolfgang Lieb, Lifelines Cohort Study, Lars Lind, Cecilia M Lindgren, Ruth J F Loos, Mary Ann Lukas, Leo-Pekka Lyytikäinen, Anubha Mahajan, Pamela R Matias-Garcia, Christa Meisinger, Thomas Meitinger, Olle Melander, Yuri Milaneschi, Pashupati P Mishra, Nina Mononen, Andrew P Morris, Josyf C Mychaleckyj, Girish N Nadkarni, Mariko Naito, Masahiro Nakatochi, Mike A Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M Nolte, Teresa Nutile, Michelle L O'Donoghue, Jeffrey O'Connell, Isleifur Olafsson, Marju Orho-Melander, Afshin Parsa, Sarah A Pendergrass, Brenda W J H Penninx, Mario Pirastu, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Olli T Raitakari, Myriam Rheinberger, Kenneth M Rice, Federica Rizzi, Alexander R Rosenkranz, Peter Rossing, Jerome I Rotter, Daniela Ruggiero, Kathleen A Ryan, Charumathi Sabanayagam, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Markus Scholz, Ben Schöttker, Christina-Alexandra Schulz, Sanaz Sedaghat, Christian M Shaffer, Karsten B Sieber, Xueling Sim, Mario Sims, Harold Snieder, Kira J Stanzick, Unnur Thorsteinsdottir, Hannah Stocker, Konstantin Strauch, Heather M Stringham, Patrick Sulem, Silke Szymczak, Kent D Taylor, Chris H L Thio, Johanne Tremblay, Simona Vaccargiu, Pim Van Der Harst, Peter J Van Der Most, Niek Verweij, Uwe Völker, Kenji Wakai, Melanie Waldenberger, Lars Wallentin, Stefan Wallner, Judy Wang, Dawn M Waterworth, Harvey D White, Cristen J Willer, Tien-Yin Wong, Mark Woodward, Qiong Yang, Laura M Yerges-Armstrong, Martina Zimmermann, Alan B Zonderman, Tobias Bergler, Kari Stefansson, Carsten A Böger, Cristian Pattaro, Anna Köttgen, Florian Kronenberg, Iris M Heid

Faculty, Staff and Student Publications

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine …

Kctd7 Deficiency Induces Myoclonic Seizures Associated With Purkinje Cell Death And Microvascular Defects, Justine H Liang, Jonathan Alevy, Viktor Akhanov, Ryan Seo, Cory A Massey, Danye Jiang, Joy Zhou, Roy V Sillitoe, Jeffrey L Noebels, Melanie A Samuel

Duncan NRI Faculty and Staff Publications

Mutations in the potassium channel tetramerization domain-containing 7 (KCTD7) gene are associated with a severe neurodegenerative phenotype characterized by childhood onset of progressive and intractable myoclonic seizures accompanied by developmental regression. KCTD7-driven disease is part of a large family of progressive myoclonic epilepsy syndromes displaying a broad spectrum of clinical severity. Animal models of KCTD7-related disease are lacking, and little is known regarding how KCTD7 protein defects lead to epilepsy and cognitive dysfunction. We characterized Kctd7 expression patterns in the mouse brain during development and show that it is selectively enriched in specific regions as the brain matures. We further …

‘Fly-Ing’ From Rare To Common Neurodegenerative Disease Mechanisms, Mengqi Ma, Matthew J Moulton, Shenzhao Lu, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Genome sequencing advances have enabled researchers and clinicians to probe vast numbers of human variants to distinguish pathogenic from benign variation. Model organisms have been critical in variant assessment and delineating molecular mechanisms of some of the diseases caused by these variants. The fruit fly, Drosophila melanogaster, has played a valuable role in this endeavor, taking advantage of its genetic technologies and established biological knowledge. In this review, we highlight the utility of the fly in studying the function of genes associated with rare neurological diseases that have led to a better understanding of common disease mechanisms. We emphasize …

Removal Of Kcnq2 From Parvalbumin-Expressing Interneurons Improves Anti-Seizure Efficacy Of Retigabine, Junzhan Jing, Corrinne Dunbar, Alina Sonesra, Ana Chavez, Suhyeorn Park, Ryan Yang, Heun Soh, Maxwell Lee, Anastasios V Tzingounis, Edward C Cooper, Xiaolong Jiang, Atul Maheshwari

Duncan NRI Faculty and Staff Publications

Anti-seizure drug (ASD) targets are widely expressed in both excitatory and inhibitory neurons. It remains unknown if the action of an ASD upon inhibitory neurons could counteract its beneficial effects on excitatory neurons (or vice versa), thereby reducing the efficacy of the ASD. Here, we examine whether the efficacy of the ASD retigabine (RTG) is altered after removal of the Kv7 potassium channel subunit KCNQ2, one of its drug targets, from parvalbumin-expressing interneurons (PV-INs). Parvalbumin-Cre (PV-Cre) mice were crossed with Kcnq2-floxed (Kcnq2fl/fl) mice to conditionally delete Kcnq2 from PV-INs. In these conditional knockout mice (cKO, PV-Kcnq2 …

Evidence For An Association Between Coffin-Siris Syndrome And Congenital Diaphragmatic Hernia, Yoel Gofin, Xiaonan Zhao, Amanda Gerard, Fernando Scaglia, Michael F Wangler, Samantha A Schrier Vergano, Daryl A Scott

Duncan NRI Faculty and Staff Publications

Coffin-Siris syndrome (CSS) is an autosomal dominant neurodevelopmental syndrome that can present with a variety of structural birth defects. Pathogenic variants in 12 genes have been shown to cause CSS. Most of these genes encode proteins that are a part of the mammalian switch/sucrose non-fermentable (mSWI/SNF; BAF) complex. An association between genes that cause CSS and congenital diaphragmatic hernia (CDH) has been suggested based on case reports and the analysis of CSS and CDH cohorts. Here, we describe an unpublished individual with CSS and CDH, and we report additional clinical information on four published cases. Data from these individuals, and …

Precision Diabetes: Lessons Learned From Maturity-Onset Diabetes Of The Young (Mody), Mustafa Tosur, Louis H Philipson

Faculty, Staff and Students Publications

Maturity-onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1-6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK-MODY, HNF1A-MODY, and HNF4A-MODY account for >90% of MODY cases. While some MODY forms do not require …

Quality Of Life, Illness Perceptions, And Parental Lived Experiences In Tango2-Related Metabolic Encephalopathy And Arrhythmias, Chaya N Murali, Seema R Lalani, Mahshid S Azamian, Christina Y Miyake, Hadley Stevens Smith

Faculty, Staff and Students Publications

TANGO2 disorder is a rare genetic disease with multi-system effects that causes episodic crises. Quality of life and psychosocial effects of this rare disease have not previously been studied. To examine health-related quality of life (HRQoL), illness perceptions, and lived experience, we surveyed 16 children and 31 parents of children with TANGO2 disorder identified via a disease-specific social media group and research foundation email distribution list. We assessed HRQoL by parent proxy-report and child self-report using the Pediatric Quality of Life Inventory (PedsQL™). Parental perceptions of their child's condition were assessed using the revised illness perceptions questionnaire adapted for TANGO2 …

Recommendations For Whole Genome Sequencing In Diagnostics For Rare Diseases, Erika Souche, Sergi Beltran, Erwin Brosens, John W Belmont, Magdalena Fossum, Olaf Riess, Christian Gilissen, Amin Ardeshirdavani, Gunnar Houge, Marielle Van Gijn, Jill Clayton-Smith, Matthis Synofzik, Nicole De Leeuw, Zandra C Deans, Yasemin Dincer, Sebastian H Eck, Saskia Van Der Crabben, Meena Balasubramanian, Holm Graessner, Marc Sturm, Helen Firth, Alessandra Ferlini, Rima Nabbout, Elfride De Baere, Thomas Liehr, Milan Macek, Gert Matthijs, Hans Scheffer, Peter Bauer, Helger G Yntema, Marjan M Weiss

Center for Medical Ethics and Health Policy Staff Publications

In 2016, guidelines for diagnostic Next Generation Sequencing (NGS) have been published by EuroGentest in order to assist laboratories in the implementation and accreditation of NGS in a diagnostic setting. These guidelines mainly focused on Whole Exome Sequencing (WES) and targeted (gene panels) sequencing detecting small germline variants (Single Nucleotide Variants (SNVs) and insertions/deletions (indels)). Since then, Whole Genome Sequencing (WGS) has been increasingly introduced in the diagnosis of rare diseases as WGS allows the simultaneous detection of SNVs, Structural Variants (SVs) and other types of variants such as repeat expansions. The use of WGS in diagnostics warrants the re-evaluation …

Association Of Methylenetetrahydrofolate Reductase Rs1801133 Genetic Variants With Type 2 Diabetes Mellitus And Diabetic Nephropathy, Aysegul Bayramoglu, Gokhan Bayramoglu, Halil Ibrahım Guler, Nezaket Coban, Mustafa Çagatay Korkmaz

Makara Journal of Health Research

Background: Type 2 diabetes mellitus (T2DM) is a complex metabolic disease with a genetic predisposition. Methylenetetrahydrofolatereductase (MTHFR) gene is one of the candidate genes associated with T2DM and diabetic nephropathy (DN). This research was carried out to determine the frequency of the C677T polymorphism (rs1801133) of the MTHFR gene and examine the role of rs1801133 polymorphism in T2DM and DN development.

Methods: DNA was obtained from peripheral blood samples (273 samples) using a DNA isolation kit. MTHFR rs1801133 polymorphism was determined using polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), and electrophoresis. PCR products were cut by …

Changes In Apparent Diffusion Coefficient (Adc) In Serial Weekly Mri During Radiotherapy In Patients With Head And Neck Cancer: Results From The Predict-Hn Study, Sweet Ping Ng, Carlos E Cardenas, Houda Bahig, Baher Elgohari, Jihong Wang, Jason M Johnson, Amy C Moreno, Shalin J Shah, Adam S Garden, Jack Phan, G Brandon Gunn, Steven J Frank, Yao Ding, Lumine Na, Ying Yuan, Diana Urbauer, Abdallah S R Mohamed, David I Rosenthal, William H Morrison, Michael P Macmanus, Clifton D Fuller

Faculty, Staff and Student Publications

Background: The PREDICT-HN study aimed to systematically assess the kinetics of imaging MR biomarkers during head and neck radiotherapy.

Methods: Patients with intact squamous cell carcinoma of the head and neck were enrolled. Pre-, during, and post-treatment MRI were obtained. Serial GTV and ADC measurements were recorded. The correlation between each feature and the GTV was calculated using Spearman’s correlation coefficient. The linear mixed model was used to evaluate the change in GTV over time.

Results: A total of 41 patients completed the study. The majority (76%) had oropharyngeal cancer. A total of 36 patients had intact primary tumours that …

Endophenotype Effect Sizes Support Variant Pathogenicity In Monogenic Disease Susceptibility Genes, Jennifer L Halford, Valerie N Morrill, Seung Hoan Choi, Sean J Jurgens, Giorgio Melloni, Nicholas A Marston, Lu-Chen Weng, Victor Nauffal, Amelia W Hall, Sophia Gunn, Christina A Austin-Tse, James P Pirruccello, Shaan Khurshid, Heidi L Rehm, Emelia J Benjamin, Eric Boerwinkle, Jennifer A Brody, Adolfo Correa, Brandon K Fornwalt, Namrata Gupta, Christopher M Haggerty, Stephanie Harris, Susan R Heckbert, Charles C Hong, Charles Kooperberg, Henry J Lin, Ruth J F Loos, Braxton D Mitchell, Alanna C Morrison, Wendy Post, Bruce M Psaty, Susan Redline, Kenneth M Rice, Stephen S Rich, Jerome I Rotter, Peter F Schnatz, Elsayed Z Soliman, Nona Sotoodehnia, Eugene K Wong, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Marc S Sabatine, Christian T Ruff, Kathryn L Lunetta, Patrick T Ellinor, Steven A Lubitz

Faculty, Staff and Student Publications

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

Molecular Analysis Of Short- Versus Long-Term Survivors Of High-Grade Serous Ovarian Carcinoma, Elaine Stur, Emine Bayraktar, Graziela Zibetti Dal Molin, Sherry Y Wu, Lingegowda S Mangala, Hui Yao, Ying Wang, Prahlad T Ram, Sara Corvigno, Hu Chen, Han Liang, Shelley S Tworoger, Douglas A Levine, Susan K Lutgendorf, Jinsong Liu, Kathleen N Moore, Keith A Baggerly, Beth Y Karlan, Anil K Sood

Faculty, Staff and Student Publications

Despite having similar histologic features, patients with high-grade serous ovarian carcinoma (HGSC) often experience highly variable outcomes. The underlying determinants for long-term survival (LTS, ≥10 years) versus short-term survival (STS, < 3 years) are largely unknown. The present study sought to identify molecular predictors of LTS for women with HGSC. A cohort of 24 frozen HGSC samples was collected (12 LTS and 12 STS) and analyzed at DNA, RNA, and protein levels. OVCAR5 and OVCAR8 cell lines were used for in vitro validation studies. For in vivo studies, we injected OVCAR8 cells into the peritoneal cavity of female athymic nude mice. From RNAseq analysis, 11 genes were found to be differentially expressed between the STS and LTS groups (fold change > 2; false discovery rate < 0.01). In the subsequent validation cohort, transmembrane protein 62 (TMEM62) was found to be related to LTS. CIBERSORT analysis showed that T cells (follicular helper) were found at higher levels in tumors from LTS than STS groups. In vitro data using OVCAR5 and OVCAR8 cells showed decreased proliferation with TMEM62 overexpression and positive correlation with a longevity-regulating pathway (KEGG HSA04213) at the RNA level. In vivo analysis using the OVCAR8-TMEM62-TetON model showed decreased tumor burden in mice with high- vs. low-expressing TMEM62 tumors. Our results demonstrate that restoring TMEM62 may be a novel approach for treatment of HGSC. These findings may have implications for biomarker and intervention strategies to help improve patient outcomes

Contributions Of Circulating Micrornas For Early Detection Of Lung Cancer, Jody Vykoukal, Johannes F Fahrmann, Nikul Patel, Masayoshi Shimizu, Edwin J Ostrin, Jennifer B Dennison, Cristina Ivan, Gary E Goodman, Mark D Thornquist, Matt J Barnett, Ziding Feng, George A Calin, Samir M Hanash

Faculty, Staff and Student Publications

There is unmet need to develop circulating biomarkers that would enable earlier interception of lung cancer when more effective treatment options are available. Here, a set of 30 miRNAs, selected from a review of the published literature were assessed for their predictive performance in identifying lung cancer cases in the pre-diagnostic setting. The 30 miRNAs were assayed using sera collected from 102 individuals diagnosed with lung cancer within one year following blood draw and 212 controls matched for age, sex, and smoking status. The additive performance of top-performing miRNA candidates in combination with a previously validated four-protein marker panel (4MP) …

Evaluation Of Vicinity-Based Hidden Markov Models For Genotype Imputation, Su Wang, Miran Kim, Xiaoqian Jiang, Arif Ozgun Harmanci

Faculty, Staff and Student Publications

BACKGROUND: The decreasing cost of DNA sequencing has led to a great increase in our knowledge about genetic variation. While population-scale projects bring important insight into genotype-phenotype relationships, the cost of performing whole-genome sequencing on large samples is still prohibitive. In-silico genotype imputation coupled with genotyping-by-arrays is a cost-effective and accurate alternative for genotyping of common and uncommon variants. Imputation methods compare the genotypes of the typed variants with the large population-specific reference panels and estimate the genotypes of untyped variants by making use of the linkage disequilibrium patterns. Most accurate imputation methods are based on the Li-Stephens hidden Markov …

Pancancer Analysis Of A Potential Gene Mutation Model In The Prediction Of Immunotherapy Outcomes, Lishan Yu, Caifeng Gong

Faculty, Staff and Student Publications

Background: Immune checkpoint blockade (ICB) represents a promising treatment for cancer, but predictive biomarkers are needed. We aimed to develop a cost-effective signature to predict immunotherapy benefits across cancers.

Methods: We proposed a study framework to construct the signature. Specifically, we built a multivariate Cox proportional hazards regression model with LASSO using 80% of an ICB-treated cohort (n = 1661) from MSKCC. The desired signature named SIGP was the risk score of the model and was validated in the remaining 20% of patients and an external ICB-treated cohort (n = 249) from DFCI.

Results: SIGP was based on …

Cancer-Driving Mutations Are Enriched In Genic Regions Intolerant To Germline Variation, Dimitrios Vitsios, Ryan S Dhindsa, Dorota Matelska, Jonathan Mitchell, Xuequing Zou, Joshua Armenia, Fengyuan Hu, Quanli Wang, Ben Sidders, Andrew R Harper, Slavé Petrovski

Duncan NRI Faculty and Staff Publications

Large reference datasets of protein-coding variation in human populations have allowed us to determine which genes and genic subregions are intolerant to germline genetic variation. There is also a growing number of genes implicated in severe Mendelian diseases that overlap with genes implicated in cancer. We hypothesized that cancer-driving mutations might be enriched in genic subregions that are depleted of germline variation relative to somatic variation. We introduce a new metric, OncMTR (oncology missense tolerance ratio), which uses 125,748 exomes in the Genome Aggregation Database (gnomAD) to identify these genic subregions. We demonstrate that OncMTR can significantly predict driver mutations …

Terrestrial Health Applications Of Visual Assessment Technology And Machine Learning In Spaceflight Associated Neuro-Ocular Syndrome, Joshua Ong, Alireza Tavakkoli, Nasif Zaman, Sharif Amit Kamran, Ethan Waisberg, Nikhil Gautam, Andrew G Lee

Faculty, Staff and Student Publications

The neuro-ocular effects of long-duration spaceflight have been termed Spaceflight Associated Neuro-Ocular Syndrome (SANS) and are a potential challenge for future, human space exploration. The underlying pathogenesis of SANS remains ill-defined, but several emerging translational applications of terrestrial head-mounted, visual assessment technology and machine learning frameworks are being studied for potential use in SANS. To develop such technology requires close consideration of the spaceflight environment which is limited in medical resources and imaging modalities. This austere environment necessitates the utilization of low mass, low footprint technology to build a visual assessment system that is comprehensive, accessible, and efficient. In this …

Klf5 Governs Sphingolipid Metabolism And Barrier Function Of The Skin, Ying Lyu, Yinglu Guan, Lisa Deliu, Ericka Humphrey, Joanna K Frontera, Youn Joo Yang, Daniel Zamler, Kun Hee Kim, Vakul Mohanty, Kevin Jin, Vakul Mohanty, Virginia Liu, Jinzhuang Dou, Lucas J Veillon, Shwetha V Kumar, Philip L Lorenzi, Yang Chen, Kathleen M Mcandrews, Sergei Grivennikov, Xingzhi Song, Jianhua Zhang, Yuanxin Xi, Jing Wang, Ken Chen, Priyadharsini Nagarajan, Yejing Ge

Faculty, Staff and Student Publications

Stem cells are fundamental units of tissue remodeling whose functions are dictated by lineage-specific transcription factors. Home to epidermal stem cells and their upward-stratifying progenies, skin relies on its secretory functions to form the outermost protective barrier, of which a transcriptional orchestrator has been elusive. KLF5 is a Krüppel-like transcription factor broadly involved in development and regeneration whose lineage specificity, if any, remains unclear. Here we report KLF5 specifically marks the epidermis, and its deletion leads to skin barrier dysfunction in vivo. Lipid envelopes and secretory lamellar bodies are defective in KLF5-deficient skin, accompanied by preferential loss of complex sphingolipids. …

The Microrna Processor Drosha Is A Candidate Gene For A Severe Progressive Neurological Disorder, Scott Barish, Mumine Senturk, Kelly Schoch, Amanda L Minogue, Diego Lopergolo, Chiara Fallerini, Jake Harland, Jacob H Seemann, Nicholas Stong, Peter G Kranz, Sujay Kansagra, Mohamad A Mikati, Joan Jasien, Mays El-Dairi, Paolo Galluzzi, Francesca Ariani, Alessandra Renieri, Francesca Mari, Michael F Wangler, Swathi Arur, Yong-Hui Jiang, Shinya Yamamoto, Vandana Shashi, Hugo J Bellen

Faculty, Staff and Students Publications

DROSHA encodes a ribonuclease that is a subunit of the Microprocessor complex and is involved in the first step of microRNA (miRNA) biogenesis. To date, DROSHA has not yet been associated with a Mendelian disease. Here, we describe two individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. DROSHA is constrained for missense variants and moderately intolerant to loss-of-function (o/e = 0.24). The loss of the fruit fly ortholog drosha causes developmental arrest and death in third instar larvae, a severe reduction in brain size and loss …

The Genetic Contribution To Solving The Cocktail-Party Problem, Samuel R. Mathias, Emma Knowles, Josephine Mollon, Amanda Rodrigue, Mary K. Woolsey, Rene L. Olvera, Juan M. Peralta, Satish Kumar, Harald H. H. Goring, Ravi Duggirala, Joanne E. Curran, John Blangero, David C. Glahn

School of Medicine Publications

Communicating in everyday situations requires solving the cocktail-party problem, or segregating the acoustic mixture into its constituent sounds and attending to those of most interest. Humans show dramatic variation in this ability, leading some to experience real-world problems irrespective of whether they meet criteria for clinical hearing loss. Here, we estimated the genetic contribution to cocktail-party listening by measuring speech-reception thresholds (SRTs) in 425 people from large families and ranging in age from 18 to 91 years. Roughly half the variance of SRTs was explained by genes (h 2 = 0.567). The genetic correlation between SRTs and hearing thresholds …