Genetic Phenomena Commons^™

A Neoantigen Vaccine Generates Antitumour Immunity In Renal Cell Carcinoma, David A Braun, Giorgia Moranzoni, Vipheaviny Chea, Bradley A Mcgregor, Eryn Blass, Chloe R Tu, Allison P Vanasse, Cleo Forman, Juliet Forman, Alexander B Afeyan, Nicholas R Schindler, Yiwen Liu, Shuqiang Li, Jackson Southard, Steven L Chang, Michelle S Hirsch, Nicole R Leboeuf, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Keerthi Shetty, Susan Klaeger, Siranush Sarkizova, Christina B Pedersen, Matthew Mossanen, Isabel Carulli, Anna Tarren, Joseph Duke-Cohan, Alexis A Howard, J Bryan Iorgulescu, Bohoon Shim, Jeremy M Simon, Sabina Signoretti, Jon C Aster, Liudmila Elagina, Steven A Carr, Ignaty Leshchiner, Gad Getz, Stacey Gabriel, Nir Hacohen, Lars R Olsen, Giacomo Oliveira, Donna S Neuberg, Kenneth J Livak, Sachet A Shukla, Edward F Fritsch, Catherine J Wu, Derin B Keskin, Patrick A Ott, Toni K Choueiri

Faculty, Staff and Student Publications

Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens1-6. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden. Here we conducted a phase I trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 …

Exome Sequencing Identifies Helb As A Novel Susceptibility Gene For Non-Mucinous, Non-High-Grade-Serous Epithelial Ovarian Cancer, Ed M Dicks, Jonthan P Tyrer, Suzana Ezquina, Michelle Jones, John Baierl, Pei-Chen Peng, Michael Diaz, Ellen Goode, Stacey J Winham, Thilo Dörk, Toon Van Gorp, Anna De Fazio, David D L Bowtell, Dale W Garsed, Kunle Odunsi, Kirsten Moysich, Marina Pavanello, Florentia Fostira, Penelope M Webb, Jana Soukupová, Paul A Cohen, Weiva Sieh, Renée Turzanski Fortner, Charite Ricker, Beth Karlan, Ian Campbell, James D Brenton, Susan J Ramus, Simon A Gayther, Paul D P Pharoah

Faculty, Staff and Student Publications

Rare, germline loss-of-function variants in a handful of DNA repair genes are associated with epithelial ovarian cancer. The aim of this study was to evaluate the role of rare, coding, loss-of-function variants across the genome in epithelial ovarian cancer. We carried out a gene-by-gene burden test with various histotypes using data from 2573 non-mucinous cases and 13,923 controls. Twelve genes were associated at a False Discovery Rate of less than 0.1 of which seven were the known ovarian cancer susceptibility genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6 and PALB2. The other five genes were OR2T35, HELB, MYO1A and GABRP which …

Immunelens Characterizes Systemic Immune Dysregulation In Aging And Cancer, Robert Bentham, Thomas P Jones, James R M Black, Carlos Martinez-Ruiz, Michelle Dietzen, Maria Litovchenko, Kerstin Thol, Thomas B K Watkins, Chris Bailey, Oriol Pich, Zhihui Zhang, Peter Van Loo, Genomics England Consortium, Tracerx Consortium, Charles Swanton, Nicholas Mcgranahan

Faculty, Staff and Student Publications

Recognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower …

Assessing Predictions On Fitness Effects Of Missense Variants In Hmbs In Cagi6, Jing Zhang, Lisa Kinch, Panagiotis Katsonis, Olivier Lichtarge, Milind Jagota, Yun S Song, Yuanfei Sun, Yang Shen, Nurdan Kuru, Onur Dereli, Ogun Adebali, Muttaqi Ahmad Alladin, Debnath Pal, Emidio Capriotti, Maria Paola Turina, Castrense Savojardo, Pier Luigi Martelli, Giulia Babbi, Rita Casadio, Fabrizio Pucci, Marianne Rooman, Gabriel Cia, Matsvei Tsishyn, Alexey Strokach, Zhiqiang Hu, Warren Van Loggerenberg, Frederick P Roth, Predrag Radivojac, Steven E Brenner, Qian Cong, Nick V Grishin

Faculty, Staff and Students Publications

This paper presents an evaluation of predictions submitted for the "HMBS" challenge, a component of the sixth round of the Critical Assessment of Genome Interpretation held in 2021. The challenge required participants to predict the effects of missense variants of the human HMBS gene on yeast growth. The HMBS enzyme, critical for the biosynthesis of heme in eukaryotic cells, is highly conserved among eukaryotes. Despite the application of a variety of algorithms and methods, the performance of predictors was relatively similar, with Kendall's tau correlation coefficients between predictions and experimental scores around 0.3 for a majority of submissions. Notably, the …

Cagi6 Id Panel Challenge: Assessment Of Phenotype And Variant Predictions In 415 Children With Neurodevelopmental Disorders (Ndds), Maria Cristina Aspromonte, Alessio Del Conte, Shaowen Zhu, Wuwei Tan, Yang Shen, Yexian Zhang, Qi Li, Maggie Haitian Wang, Giulia Babbi, Samuele Bovo, Pier Luigi Martelli, Rita Casadio, Azza Althagafi, Sumyyah Toonsi, Maxat Kulmanov, Robert Hoehndorf, Panagiotis Katsonis, Amanda Williams, Olivier Lichtarge, Su Xian, Wesley Surento, Vikas Pejaver, Sean D Mooney, Uma Sunderam, Rajgopal Srinivasan, Alessandra Murgia, Damiano Piovesan, Silvio C E Tosatto, Emanuela Leonardi

Faculty, Staff and Students Publications

The Genetics of Neurodevelopmental Disorders Lab in Padua provided a new intellectual disability (ID) Panel challenge for computational methods to predict patient phenotypes and their causal variants in the context of the Critical Assessment of the Genome Interpretation, 6th edition (CAGI6). Eight research teams submitted a total of 30 models to predict phenotypes based on the sequences of 74 genes (VCF format) in 415 pediatric patients affected by Neurodevelopmental Disorders (NDDs). NDDs are clinically and genetically heterogeneous conditions, with onset in infant age. Here, we assess the ability and accuracy of computational methods to predict comorbid phenotypes based on clinical …

Genomic Balancing Act: Deciphering Dna Rearrangements In The Complex Chromosomal Aberration Involving 5p152, 2q311, And 18q2132, Zain Dardas, Dana Marafi, Ruizhi Duan, Jawid M Fatih, Omnia F El-Rashidy, Christopher M Grochowski, Claudia M B Carvalho, Shalini N Jhangiani, Weimin Bi, Haowei Du, Richard A Gibbs, Jennifer E Posey, Daniel G Calame, Maha S Zaki, James R Lupski

Faculty, Staff and Students Publications

Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and a terminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses …

Analysis And Benchmarking Of Small And Large Genomic Variants Across Tandem Repeats, Adam C English, Egor Dolzhenko, Helyaneh Ziaei Jam, Sean K Mckenzie, Nathan D Olson, Wouter De Coster, Jonghun Park, Bida Gu, Justin Wagner, Michael A Eberle, Melissa Gymrek, Mark J P Chaisson, Justin M Zook, Fritz J Sedlazeck

Faculty, Staff and Students Publications

Tandem repeats (TRs) are highly polymorphic in the human genome, have thousands of associated molecular traits and are linked to over 60 disease phenotypes. However, they are often excluded from at-scale studies because of challenges with variant calling and representation, as well as a lack of a genome-wide standard. Here, to promote the development of TR methods, we created a catalog of TR regions and explored TR properties across 86 haplotype-resolved long-read human assemblies. We curated variants from the Genome in a Bottle (GIAB) HG002 individual to create a TR dataset to benchmark existing and future TR analysis methods. We …

Meeting Report: 1st International Conference On Polyploid Giant Cancer Cells-Biology, Clinical Applications, And The Birth Of A New Field In Cancer Research, Tao P Wu, Xiaoran Li, Sujuan Ba, Phil Jones, Donna E Hansel, Jinsong Liu

Faculty, Staff and Students Publications

No abstract provided.

Evaluation Of Enzyme Activity Predictions For Variants Of Unknown Significance In Arylsulfatase A, Shantanu Jain, Marena Trinidad, Thanh Binh Nguyen, Kaiya Jones, Santiago Diaz Neto, Fang Ge, Ailin Glagovsky, Cameron Jones, Giankaleb Moran, Boqi Wang, Kobra Rahimi, Sümeyra Zeynep Çalıcı, Luis R Cedillo, Silvia Berardelli, Buse Özden, Ken Chen, Panagiotis Katsonis, Amanda Williams, Olivier Lichtarge, Sadhna Rana, Swatantra Pradhan, Rajgopal Srinivasan, Rakshanda Sajeed, Dinesh Joshi, Eshel Faraggi, Robert Jernigan, Andrzej Kloczkowski, Jierui Xu, Zigang Song, Selen Özkan, Natàlia Padilla, Xavier De La Cruz, Rocio Acuna-Hidalgo, Andrea Grafmüller, Laura T Jiménez Barrón, Matteo Manfredi, Castrense Savojardo, Giulia Babbi, Pier Luigi Martelli, Rita Casadio, Yuanfei Sun, Shaowen Zhu, Yang Shen, Fabrizio Pucci, Marianne Rooman, Gabriel Cia, Daniele Raimondi, Pauline Hermans, Sofia Kwee, Ella Chen, Courtney Astore, Akash Kamandula, Vikas Pejaver, Rashika Ramola, Michelle Velyunskiy, Daniel Zeiberg, Reet Mishra, Teague Sterling, Jennifer L Goldstein, Jose Lugo-Martinez, Sufyan Kazi, Sindy Li, Kinsey Long, Steven E Brenner, Constantina Bakolitsa, Predrag Radivojac, Dean Suhr, Teryn Suhr, Wyatt T Clark

Faculty, Staff and Students Publications

Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the Arylsulfatase A (ARSA) gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models. Notably, a model developed by participants of a genetics and coding bootcamp, trained with standard machine-learning …

Evaluating Predictors Of Kinase Activity Of Stk11 Variants Identified In Primary Human Non-Small Cell Lung Cancers, Yile Chen, Kyoungyeul Lee, Junwoo Woo, Dong-Wook Kim, Changwon Keum, Giulia Babbi, Rita Casadio, Pier Luigi Martelli, Castrense Savojardo, Matteo Manfredi, Yang Shen, Yuanfei Sun, Panagiotis Katsonis, Olivier Lichtarge, Vikas Pejaver, David J Seward, Akash Kamandula, Constantina Bakolitsa, Steven E Brenner, Predrag Radivojac, Anne O'Donnell-Luria, Sean D Mooney, Shantanu Jain

Faculty, Staff and Students Publications

Critical evaluation of computational tools for predicting variant effects is important considering their increased use in disease diagnosis and driving molecular discoveries. In the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, a dataset of 28 STK11 rare variants (27 missense, 1 single amino acid deletion), identified in primary non-small cell lung cancer biopsies, was experimentally assayed to characterize computational methods from four participating teams and five publicly available tools. Predictors demonstrated a high level of performance on key evaluation metrics, measuring correlation with the assay outputs and separating loss-of-function (LoF) variants from wildtype-like (WT-like) variants. The …

Predicting The Impact Of Rare Variants On Rna Splicing In Cagi6, Jenny Lord, Carolina Jaramillo Oquendo, Htoo A Wai, Andrew G L Douglas, David J Bunyan, Yaqiong Wang, Zhiqiang Hu, Zishuo Zeng, Daniel Danis, Panagiotis Katsonis, Amanda Williams, Olivier Lichtarge, Yuchen Chang, Richard D Bagnall, Stephen M Mount, Brynja Matthiasardottir, Chiaofeng Lin, Thomas Van Overeem Hansen, Raphael Leman, Alexandra Martins, Claude Houdayer, Sophie Krieger, Constantina Bakolitsa, Yisu Peng, Akash Kamandula, Predrag Radivojac, Diana Baralle

Faculty, Staff and Students Publications

Variants which disrupt splicing are a frequent cause of rare disease that have been under-ascertained clinically. Accurate and efficient methods to predict a variant's impact on splicing are needed to interpret the growing number of variants of unknown significance (VUS) identified by exome and genome sequencing. Here, we present the results of the CAGI6 Splicing VUS challenge, which invited predictions of the splicing impact of 56 variants ascertained clinically and functionally validated to determine splicing impact. The performance of 12 prediction methods, along with SpliceAI and CADD, was compared on the 56 functionally validated variants. The maximum accuracy achieved was …

Genomics And Multiomics In The Age Of Precision Medicine, Srinivasan Mani, Seema R Lalani, Mohan Pammi

Faculty, Staff and Students Publications

Precision medicine is a transformative healthcare model that utilizes an understanding of a person's genome, environment, lifestyle, and interplay to deliver customized healthcare. Precision medicine has the potential to improve the health and productivity of the population, enhance patient trust and satisfaction in healthcare, and accrue health cost-benefits both at an individual and population level. Through faster and cost-effective genomics data, next-generation sequencing has provided us the impetus to understand the nuances of complex interactions between genes, diet, and lifestyle that are heterogeneous across the population. The emergence of multiomics technologies, including transcriptomics, proteomics, epigenomics, metabolomics, and microbiomics, has enhanced …

Immunogenetic Studies In Patients With Gad-Positive Stiff-Person Syndrome Reveal Novel Lymphocytic Genes And Klk10 -Gene Variants, Popianna Tsiortou, Harry Alexopoulos, Konstantinos Kyriakidis, Michalis Kosmidis, Chrysanthi Barba, Sofia Akrivou, Ioannis Michalopoulos, Panagiotis Politis, Marinos Dalakas

Department of Neurology Faculty Papers

BACKGROUND AND OBJECTIVES: The aim of this study was to identify genetic markers and immunologic characteristics of glutamic acid decarboxylase (GAD) antibody-positive patients with stiff-person syndrome (SPS).

METHODS: We conducted systemic immunogenetic studies in 11 GAD-positive patients: 8 with sporadic SPS and 3 from a three-generation family with very high GAD-ab titers but diverse symptomatology (one with GAD-epilepsy and SPS and 2 only with diabetes), by performing complete immunologic profile and whole-exome sequencing analysis.

RESULTS: Two genes expressed in immune and neuronal tissues were identified: the ORAI1 that codes for a calcium release–activated channel protein with a role in the …

Muscle-Specific Errγ Activation Mitigates Muscle Atrophy After Acl Injury, Aiping Lu, Katie J Sikes, Ping Guo, Matthieu Huard, Shelbi Green, Kelly Santangelo, Jacob Singer, Ashley Groesbeck, Scott Tashman, Vihang A Narkar, Johnny Huard

Faculty, Staff and Student Publications

Anterior cruciate ligament (ACL) injury adversely affects skeletal muscle, leading to muscle atrophy and weakness, significantly impacting clinical outcomes. This study aimed to determine if estrogen-related receptor gamma (ERRγ) overexpression in skeletal muscle could mitigate muscle atrophy after ACL injury. An animal model with selective overexpression of ERRγ in skeletal muscle (ERR-gamma transgenic mice, TG) and WT control mice were used for this study. All the mice received a mechanical ACL rupture and were euthanized at 4- and 8-week post-injury. Muscle histology, atrophy, and function were evaluated and compared between the TG and WT mice. Muscle-specific ERRγ activation in TG …

New Onset Diabetes Predicts Clinical Outcomes In Patients With Pancreatic Adenocarcinoma, Chirayu Mohindroo, Paul S Dy, Suraj P Hande, Christopher R D'Adamo, Arun Mavanur, Asha Thomas, Florencia Mcallister, Ana De Jesus-Acosta

Faculty, Staff and Student Publications

Background: One percent of pancreatic adenocarcinoma (PDAC) patients are diagnosed with new onset diabetes (NOD) over the age of 50 years within 3 years. Therefore, NOD is a major factor for early diagnosis of PDAC. Research has focused on understanding the differences between NOD and type 2 diabetes, particularly in relation to PDAC. However, conflicting data exists regarding their impact on survival outcomes in PDAC patients. We performed this multi-center study to assess the prevalence and influence of NOD on clinical outcomes in patients with PDAC within a community-based hospital system.

Methods: We conducted a retrospective cohort study of 138 …

Is The Pendulum Slowly Starting To Swing Back?, Michael S Ewer, Jay Herson

Faculty, Staff and Student Publications

No abstract provided.

The Spatial Landscape Of Cancer Hallmarks Reveals Patterns Of Tumor Ecological Dynamics And Drug Sensitivity, Mustafa Sibai, Sergi Cervilla, Daniela Grases, Eva Musulen, Rossana Lazcano, Chia-Kuei Mo, Veronica Davalos, Arola Fortian, Adrià Bernat, Margarita Romeo, Collin Tokheim, Jordi Barretina, Alexander J Lazar, Li Ding, Dutreneo Study Investigators, Enrique Grande, Francisco X Real, Manel Esteller, Matthew H Bailey, Eduard Porta-Pardo

Faculty, Staff and Student Publications

Tumors are complex ecosystems of interacting cell types. The concept of cancer hallmarks distills this complexity into underlying principles that govern tumor growth. Here, we explore the spatial distribution of cancer hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that hallmark activity is spatially organized, with the cancer compartment contributing to the activity of seven out of 13 hallmarks, while the tumor microenvironment (TME) contributes to the activity of the rest. Additionally, we discover that genomic distance between tumor subclones correlates with differences in hallmark activity, even leading to clone-hallmark specialization. Finally, we …

Immunological Biomarkers Of Response And Resistance To Treatment With Cabozantinib And Nivolumab In Recurrent Endometrial Cancer, Vladimir Roudko, Diane Marie Del Valle, Emir Radkevich, Geoffrey Kelly, Xie Hui, Manishkumar Patel, Edgar Gonzalez-Kozlova, Kevin Tuballes, Howard Streicher, Swati Atale, Lisa Wang, Benito Czinczin, Seunghee Kim-Schulze, Ignacio I Wistuba, Cara L Haymaker, Gheath Al-Atrash, Ganiraju Manyam, Jianjun Zhang, Ryan Thompson, Mayte Suarez-Farinas, Stephanie Lheureux, Sacha Gnjatic

Faculty, Staff and Student Publications

Background: Antiangiogenics combined with immune checkpoint blockade have become standard of care for recurrent endometrial cancer after standard platinum-based chemotherapy. To dissect mechanisms and define biomarkers associated with clinical outcomes to these combinations, we applied multidimensional immune monitoring to peripheral blood specimens collected from a randomized phase 2 trial of nivolumab with or without cabozantinib in 75 evaluable patients with recurrent endometrial cancer (NCI ETCTN 10104, NCT03367741). This trial demonstrated superiority of the combination to nivolumab alone.

Methods and results: Using Olink proteomics, mass cytometry, tumor antigen-specific ELISA, and whole exome tumor sequencing, we identified longitudinal immune signatures specific …

Sequence Of Therapy Impact On Older Women With Comorbidities And Triple-Negative Or Her2-Positive Breast Cancer, Nina Tamirisa, Wenli Dong, Yu Shen, Heather Lin, Simona F Shaitelman, Gildy Babiera, Isabelle Bedrosian

Faculty, Staff and Student Publications

We sought to determine whether sequencing of treatment impacted outcomes in older, comorbid patients. Using the National Cancer Database(2010-2017), 2911 patients >70 with a Charleson Deyo Comorbidity(CCDM) score of 2/3 and cT1c-3/N0-3/HER2 positive or triple-negative breast cancer treated with chemotherapy,surgery,or both were included. Chi-square tests evaluated differences between groups. Multivariable models evaluated associations between overall survival and treatment. Majority 87.4%(n = 2544) underwent surgery first and 36.0%(n = 917) received adjuvant chemotherapy while 77.9%(n = 286) of chemotherapy first patients underwent surgery. Receipt of both modalities was associated with the best survival followed by surgery alone then chemotherapy alone. Additional …

Primary Intrathoracic Synovial Sarcoma: An Analysis Of Outcomes Of This Rare Disease, Riddhi R Patel, Andrew J Bishop, Alexander J Lazar, Patrick P Lin, Robert S Benjamin, Shreyaskumar R Patel, Joseph Ludwig, Vinod Ravi, Ara A Vaporciyan, Dejka M Araujo

Faculty, Staff and Student Publications

No abstract provided.

The Heterogeneity Of 13q Deletions In Chronic Lymphocytic Leukemia: Diagnostic Challenges And Clinical Implications, Changqing Xia, Guang Liu, Jinglan Liu, Arash Ronaghy, Saber Tadros, Wei Wang, Hong Fang, Shanxiang Zhang, Joseph D Khoury, Zhenya Tang

Faculty, Staff and Student Publications

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, particularly in Western countries. CLL can present indolently or aggressively, influenced by various factors, including chromosomal alterations. Fluorescent in situ hybridization (FISH), targeting specific genes/loci frequently affected in CLL patients, has established a standard for stratifying five CLL prognostic groups: del(11q)/ATM, trisomy 12, del(13q) as a sole aberration, del(17p)/TP53, and normal CLL FISH panel results. Among these, del(13q) as a sole aberration is associated with a favorable prognosis, while the others are considered intermediate (normal CLL FISH panel result and trisomy 12) or unfavorable …

Aberrant Choroid Plexus Formation Drives The Development Of Treatment-Related Brain Toxicity, Tamara Bender, Esther Schickel, Celine Schielke, Jürgen Debus, David R Grosshans, Marco Durante, Insa S Schroeder

Faculty, Staff and Student Publications

Brain tumors are commonly treated with radiotherapy, but the efficacy of the treatment is limited by its toxicity to the normal tissue including post-irradiation contrast enhanced lesions often linked to necrosis. The poorly understood mechanisms behind such brain lesions were studied using cerebral organoids. Here we show that irradiation of such organoids leads to dose-dependent growth retardation and formation of liquid-filled cavities but is not correlated with necrosis. Instead, the radiation-induced changes comprise of an enhancement of cortical hem markers, altered neuroepithelial stem cell differentiation, and an increase of ZO1+/AQP1+/CLDN3+-choroid plexus (CP)-like structures accompanied by an upregulation of IGF2 mRNA, …

Immune Checkpoint Inhibitors Plus Debulking Surgery For Patients With Metastatic Renal Cell Carcinoma: Clinical Outcomes And Immunological Correlates Of A Prospective Pilot Trial, Sangeeta Goswami, Jianjun Gao, Sreyashi Basu, Daniel D Shapiro, Jose A Karam, Rebecca Slack Tidwell, Kamran Ahrar, Matthew T Campbell, Yu Shen, Alexandro E Trevino, Aaron T Mayer, Alexsandra B Espejo, Christian Seua, Marc D Macaluso, Yulong Chen, Wenbin Liu, Zhong He, Shalini S Yadav, Ying Wang, Priya Rao, Li Zhao, Jianhua Zhang, Sonali Jindal, Nizar M Tannir, Andrew Futreal, Linghua Wang, Padmanee Sharma

Faculty, Staff and Student Publications

Surgical removal of primary tumors reverses tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT), is not understood. We report the first prospective, pilot, non-comparative clinical trial (NCT02210117) to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma. Primary safety endpoint of this trial has been met, with 43 patients completing cytoreductive surgery, 36 patients undergoing …

The Bacterial Microbiome Modulates The Initiation Of Brain Metastasis By Impacting The Gut-To-Brain Axis, Matteo Massara, Michelle Ballabio, Bastien Dolfi, Golnaz Morad, Vladimir Wischnewski, Eleni Lamprou, Joao Lourenco, Stéphanie Claudinot, Hector Gallart-Ayala, Rui Santalla Méndez, Annamaria Kauzlaric, Nadine Fournier, Ashish V Damania, Matthew C Wong, Julijana Ivanisevic, Nadim J Ajami, Jennifer A Wargo, Johanna A Joyce

Faculty, Staff and Student Publications

Brain metastases (BrMs) are the most common brain tumors in patients and are associated with poor prognosis. Investigating the systemic and environmental factors regulating BrM biology represents an important strategy to develop effective treatments. Toward this goal, we explored the contribution of the gut microbiome to BrM development by using in vivo breast-BrM models under germ-free conditions or antibiotic treatment. This revealed a detrimental role of gut microbiota in fostering BrM initiation. We thus evaluated the impact of antibiotics and BrM outgrowth on the gut-brain axis. We found the bacterial genus Alistipes was differentially present under antibiotic treatment and BrM …

Antibiotic-Induced Loss Of Gut Microbiome Metabolic Output Correlates With Clinical Responses To Car T-Cell Therapy, Rishika Prasad, Abdur Rehman, Lubna Rehman, Faezeh Darbaniyan, Viktoria Blumenberg, Maria-Luisa Schubert, Uria Mor, Eli Zamir, Sabine Schmidt, Tomo Hayase, Chia-Chi Chang, Lauren Mcdaniel, Ivonne Flores, Paolo Strati, Ranjit Nair, Dai Chihara, Luis E Fayad, Sairah Ahmed, Swaminathan P Iyer, Michael Wang, Preetesh Jain, Loretta J Nastoupil, Jason Westin, Reetakshi Arora, Joel Turner, Fareed Khawaja, Ranran Wu, Jennifer B Dennison, Meghan Menges, Melanie Hidalgo-Vargas, Kayla Reid, Marco L Davila, Peter Dreger, Felix Korell, Anita Schmitt, Mark R Tanner, Richard E Champlin, Christopher R Flowers, Elizabeth J Shpall, Samir Hanash, Sattva S Neelapu, Michael Schmitt, Marion Subklewe, Johannes Francois-Fahrmann, C K Stein-Thoeringer, Eran Elinav, Michael D Jain, Eiko Hayase, Robert R Jenq, Neeraj Y Saini

Faculty, Staff and Student Publications

Antibiotic (ABX)–induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies. In this study, we observed that prior exposure to broad-spectrum ABXs with extended anaerobic coverage such as piperacillin-tazobactam and meropenem was associated with worse anti-CD19 CAR-T therapy survival outcomes in patients with large B-cell lymphoma (N = 422) than other ABX classes. In a discovery subset of these patients (n = 67), we found that the use of these ABXs was in turn associated with substantial dysbiosis of gut microbiome function, …

Aif3 Splicing Variant Elicits Mitochondrial Malfunction Via The Concurrent Dysregulation Of Electron Transport Chain And Glutathione-Redox Homeostasis, Mi Zhou, Shuiqiao Liu, Yanan Wang, Bo Zhang, Ming Zhu, Jennifer E Wang, Veena Rajaram, Yisheng Fang, Weibo Luo, Yingfei Wang

Faculty, Staff and Student Publications

Genetic mutations in apoptosis-inducing factor (AIF) have a strong association with mitochondrial disorders; however, little is known about the aberrant splicing variants in affected patients and how these variants contribute to mitochondrial dysfunction and brain development defects. We identified pathologic AIF3/AIF3-like splicing variants in postmortem brain tissues of pediatric individuals with mitochondrial disorders. Mutations in AIFM1 exon-2/3 increase splicing risks. AIF3-splicing disrupts mitochondrial complexes, membrane potential, and respiration, causing brain development defects. Mechanistically, AIF is a mammalian NAD(P)H dehydrogenase and possesses glutathione reductase activity controlling respiratory chain functions and glutathione regeneration. Conversely, AIF3, lacking these activities, disassembles mitochondrial complexes, increases …

Development Of A Conditional Plasmid For Gene Deletion In Non-Model Fusobacterium Nucleatum Strains, Peng Zhou, Bibek G C, Chenggang Wu

Faculty, Staff and Student Publications

Fusobacterium nucleatum is an opportunistic pathogen with four subspecies: nucleatum (FNN), vincentii (FNV), polymorphum (FNP), and animalis (FNA), each with distinct disease potentials. Research on fusobacterial pathogenesis has mainly focused on the model strain ATCC 23726 from FNN. However, this narrow focus may overlook significant behaviors of other FNN strains and those from other subspecies, given the genetic and phenotypic diversity within F. nucleatum. While ATCC 23726 is highly transformable, most other Fusobacterium strains exhibit low transformation efficiency, complicating traditional gene deletion methods that rely on non-replicating plasmids. To address this, we developed a conditional plasmid system in which …

Early Application Value Of Flexible Laryngoscope Swallowing Function Assessment In Patients After Partial Laryngectomy, Lina Jia, Chenxu Yan, Run Liu, Pengfei He, Ailing Liu, Fei Yang, Hui Huangfu, Sen Zhang

Faculty, Staff and Student Publications

To investigate the influence of early dysphagia on quality of life in patients with partial laryngectomy, and to investigate the application value of Flexible Endoscopic Evaluation of Swallowing (FEES). This study included 30 inpatients who underwent partial laryngectomy due to laryngeal cancer. In the early postoperative period, a comprehensive assessment was conducted on each patient, encompassing Videofluoroscopic Swallowing Study (VFSS), Flexible Endoscopic Evaluation of Swallowing (FEES), and MD Anderson Dysphagia Inventory (MDADI). Each patient underwent two evaluations at different time points following the surgical procedure, all conducted on the same day. The patients' first MDADI assement score after surgery was …

Assessing The Contribution Of Rare Protein-Coding Germline Variants To Prostate Cancer Risk And Severity In 37,184 Cases, Jonathan Mitchell, Niedzica Camacho, Patrick Shea, Konrad H Stopsack, Vijai Joseph, Oliver S Burren, Ryan S Dhindsa, Abhishek Nag, Jacob E Berchuck, Amanda O'Neill, Ali Abbasi, Anthony W Zoghbi, Jesus Alegre-Díaz, Pablo Kuri-Morales, Jaime Berumen, Roberto Tapia-Conyer, Jonathan Emberson, Jason M Torres, Rory Collins, Quanli Wang, David Goldstein, Athena Matakidou, Carolina Haefliger, Lauren Anderson-Dring, Ruth March, Vaidehi Jobanputra, Brian Dougherty, Keren Carss, Slavé Petrovski, Philip W Kantoff, Kenneth Offit, Lorelei A Mucci, Mark Pomerantz, Margarete A Fabre

Faculty, Staff and Students Publications

To assess the contribution of rare coding germline genetic variants to prostate cancer risk and severity, we perform here a meta-analysis of 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline whole exome or genome sequencing data, and one cohort with imputed array data. At the gene level, our case-control collapsing analysis confirms associations between rare damaging variants in four genes and increased prostate cancer risk: SAMHD1, BRCA2 and ATM at the study-wide significance level (P <  1×10−8), and CHEK2 at the suggestive threshold (P <  2.6×10−6). Our case-only analysis, reveals that rare damaging variants in AOX1 are associated with more aggressive disease (OR = 2.60 [1.75–3.83], …

Iroc Phantoms Accurately Detect Mlc Delivery Errors, Sharbacha S Edward, Julianne M Pollard-Larkin, Peter A Balter, Rebecca M Howell, Christine B Peterson, Stephen F Kry

Faculty, Staff and Student Publications

Purpose: We evaluated the impact of random and whole-bank multileaf collimator (MLC) delivery errors on dosimetric delivery accuracy in the Imaging and Radiation Oncology Core (IROC) phantom audits, as well as differences in delivery accuracy between the IROC phantom prescription and typical clinical fraction sizes.

Methods and materials: Plans were created for the IROC IMRT head and neck (H&N) and SBRT spine phantoms. MLC leaf errors were introduced into the plans: random shifts between -2 and 2 mm, and whole bank shifts of 0.5, 1, and 2 mm. Plans were recalculated and delivered on a Varian Truebeam, and the log …