Medical Specialties Commons^™

Targeted Degradation Of Oncogenic Krasg12v Triggers Antitumor Immunity In Lung Cancer Models, Dezhi Li, Ke Geng, Yuan Hao, Jiajia Gu, Saurav Kumar, Annabel T Olson, Christina C Kuismi, Hye Mi Kim, Yuanwang Pan, Fiona Sherman, Asia M Williams, Yiting Li, Fei Li, Ting Chen, Cassandra Thakurdin, Michela Ranieri, Mary Meynardie, Daniel S Levin, Janaye Stephens, Alison Chafitz, Joy Chen, Mia S Donald-Paladino, Jaylen M Powell, Ze-Yan Zhang, Wei Chen, Magdalena Ploszaj, Han Han, Shengqing Stan Gu, Tinghu Zhang, Baoli Hu, Benjamin A Nacev, Medard Ernest Kaiza, Alice H Berger, Xuerui Wang, Jing Li, Xuejiao Sun, Yang Liu, Xiaoyang Zhang, Tullia C Bruno, Nathanael S Gray, Behnam Nabet, Kwok-Kin Wong, Hua Zhang

Faculty, Staff and Student Publications

Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V-transgenic mouse model. We explored the therapeutic potential of KRASG12V degradation and characterized its effect on the tumor microenvironment (TME). …

Phenotypic And Genetic Heterogeneity Of A Pakistani Cohort Of 15 Consanguineous Families Segregating Variants In Leber Congenital Amaurosis-Associated Genes, Zainab Akhtar, Sumaira Altaf, Yumei Li, Sana Bibi, Jamal Shah, Kiran Afshan, Meng Wang, Hafiz Muhammad Jafar Hussain, Nadeem Qureshi, Rui Chen, Sabika Firasat

Faculty, Staff and Students Publications

Background: Leber congenital amaurosis (LCA) is a congenital onset severe form of inherited retinal dystrophy (IRD) and a common cause of pediatric blindness. Disease-causing variants in at least 14 genes are reported to predispose LCA phenotype. LCA is inherited as an autosomal recessive disease. It can be an isolated eye disorder or as part of a syndrome, such as Senior Loken or Joubert syndrome. Sequencing studies from consanguineous populations have proven useful for novel variants identification; thus, the present study aimed to explore the genetic heterogeneity of 15 consanguineous Pakistani families, each segregating a severe IRD phenotype using targeted next …

Enhancer Reprogramming Underlies Therapeutic Utility Of A Smarca2 Degrader In Smarca4 Mutant Cancer, Sasikumar Kotagiri, Nicholas Blazanin, Yuanxin Xi, Yanyan Han, Md Qudratullah, Xiaobing Liang, Yawen Wang, Poonam Pandey, Hira Mazhar, Truong Nguyen Lam, Anand Kamal Singh, Jing Wang, Yonathan Lissanu

Faculty, Staff and Student Publications

Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes …

Mutation- And Mrd-Informed Treatments For Transplant-Ineligible Patients, Curtis A Lachowiez, Courtney D Dinardo

Faculty, Staff and Student Publications

The ongoing development of molecularly targeted therapies in addition to the new standard of care combination of azacitidine and venetoclax (AZA-VEN) has transformed the prognostic outlook for older, transplant-ineligible patients with acute myeloid leukemia (AML). While conventional treatments, such as standard anthracycline and cytarabine- based chemotherapy or hypomethylating agent (HMA) monotherapy, are associated with a generally poor prognosis in this patient population, the use of these novel regimens can result in long-lasting, durable remissions in select patient subgroups. Furthermore, the simultaneous discovery of resistance mechanisms to targeted therapies and AZA-VEN has enabled the identification of patient subgroups with inferior outcomes, …

Clonal Landscape And Clinical Outcomes Of Telomere Biology Disorders: Somatic Rescue And Cancer Mutations, Fernanda Gutierrez-Rodrigues, Emma M Groarke, Natthakan Thongon, Juan Jose Rodriguez-Sevilla, Luiz Fernando B Catto, Marena R Niewisch, Ruba Shalhoub, Lisa J Mcreynolds, Diego V Clé, Bhavisha A Patel, Xiaoyang Ma, Dalton Hironaka, Flávia S Donaires, Nina Spitofsky, Barbara A Santana, Tsung-Po Lai, Lemlem Alemu, Sachiko Kajigaya, Ivana Darden, Weiyin Zhou, Paul V Browne, Subrata Paul, Justin Lack, David J Young, Courtney D Dinardo, Abraham Aviv, Feiyang Ma, Michel Michels De Oliveira, Ana Paula De Azambuja, Cynthia E Dunbar, Malgorzata Olszewska, Emmanuel Olivier, Eirini P Papapetrou, Neelam Giri, Blanche P Alter, Carmem Bonfim, Colin O Wu, Guillermo Garcia-Manero, Sharon A Savage, Neal S Young, Simona Colla, Rodrigo T Calado

Faculty, Staff and Student Publications

Telomere biology disorders (TBDs), caused by pathogenic germ line variants in telomere-related genes, present with multiorgan disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBDs is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 patients with TBD with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, …

Immune Landscape Of Isocitrate Dehydrogenase-Stratified Primary And Recurrent Human Gliomas, Pravesh Gupta, Minghao Dang, Shivangi Oberai, Simona Migliozzi, Rakesh Trivedi, Gayatri Kumar, Mekenzie Peshoff, Nancy Milam, Aml Ahmed, Krishna Bojja, Tuan M Tran, Joy Gumin, Carlos Kamiya-Matsuoka, Jason Huse, Kathryn Cox, Jianzhuo Li, Huma Shehwana, Sameer A Sheth, Rodriguez Saxon, Sun Baohua, Brittany Parker Kerrigan, Atul Maheshwari, Edwin Roger Parra Cuentas, Nicholas E Navin, Amy B Heimberger, Frederick F Lang, Antonio Iavarone, Karen Clise-Dwyer, Linghua Wang, Krishna P Bhat

Faculty, Staff and Student Publications

Background: Human gliomas are classified using isocitrate dehydrogenase (IDH) status as a prognosticator; however, the influence of genetic differences and treatment effects on ensuing immunity remains unclear.

Methods: In this study, we used sequential single-cell transcriptomics on 144 678 and spectral cytometry on over 2 million immune cells encompassing 48 human gliomas to decipher their immune landscape.

Results: We identified 22 distinct immune cell types that contribute to glioma immunity. Specifically, brain-resident microglia (MG) were reduced with a concomitant increase in CD8+ T lymphocytes during glioma recurrence independent of IDH status. In contrast, IDH-wild type-associated patterns, such as an abundance …

Onset And Progression Of Disease In Nonhuman Primates With Pde6c Cone Disorder, Monica Ardon, Lily Nguyen, Rui Chen, Jeffrey Rogers, Tim Stout, Sara Thomasy, Ala Moshiri

Faculty, Staff and Students Publications

PURPOSE: The California National Primate Research Center contains a colony of rhesus macaques with a homozygous missense mutation in PDE6C (R565Q) which causes a cone disorder similar to PDE6C achromatopsia in humans. The purposes of this study are to characterize the phenotype in PDE6C macaques in detail to determine the onset of the cone phenotype, the degree to which the phenotype progresses, if heterozygote animals have an intermediate phenotype, and if rod photoreceptor function declines over time.

METHODS: We analyzed spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and electroretinography (ERG) data from 102 eyes of 51 macaques (aged 0.25 …

Rna Shielding Of P65 Is Required To Potentiate Oncogenic Inflammation In Tet2-Mutated Clonal Hematopoiesis, Nana Adjoa Ben-Crentsil, Wazim Mohammed Ismail, Maria E Balasis, Hannah Newman, Ariel Quintana, Moritz Binder, Traci Kruer, Surendra Neupane, Meghan C Ferrall-Fairbanks, Jenna Fernandez, Terra L Lasho, Christy M Finke, Mohammed L Ibrahim, Kathy L Mcgraw, Michael Wysota, Amy L Aldrich, Christopher B Ryder, Christopher T Letson, Joshua Traina, Amy F Mclemore, Nathalie Droin, Aditi Shastri, Seongseok Yun, Eric Solary, David A Sallman, Amer A Beg, Li Ma, Alexandre Gaspar-Maia, Mrinal M Patnaik, Eric Padron

Faculty, Staff and Student Publications

This work identifies MALAT1 as a requisite downstream effector of oncogenic feedforward inflammatory circuits necessary for the development of TET2-mutated CH and fulminant myeloid malignancy. We elucidate a novel mechanism by which MALAT1 "shields" p65 from dephosphorylation to potentiate this circuit and nominate MALAT1 inhibition as a future therapeutic strategy.

Mecp2 Variants In Males: More Common Than Previously Appreciated, Amitha Ananth, Cary Fu, Jeffrey L Neul, Tim Benke, Eric Marsh, Bernhard Suter, Kathleen Ferdinandsen, Steven A Skinner, Fran Annese, Alan K Percy

Faculty, Staff and Students Publications

Background: To assess the age and MECP2 variants of recently identified males and set the stage for further study of clinical features in males.

Methods: Genetic information on the specific MECP2 variant was acquired from the coordinator (K.F.) of the Parent Group for Males. Data were collected indicating whether these variants were de novo or transmitted from the mother and whether males who appeared to meet the diagnostic criteria for Rett syndrome had mosaicism for the MECP2 variant.

Results: Fifty-nine males were identified through the parent group. Their ages ranged from 2 to 28 years, with the median age being …

Testosterone Acts Through The Membrane Protein Gprc6a To Cause Cardiac Edema In Zebrafish Embryos, Vahid Zadmajid, Shayan Shahriar, Daniel A Gorelick

Faculty, Staff and Students Publications

Androgens are classically thought to act through intracellular androgen receptors (AR/NR3C4), but they can also trigger non-genomic effects via membrane proteins. Although several membrane androgen receptors have been characterized in vitro, their functions in vivo remain unclear. Using a chemical-genetic screen in zebrafish, we found that GPRC6A, a G-protein-coupled receptor, mediates non-genomic androgen actions during embryonic development. Exposure to androgens (androstanedione, DHT and testosterone) caused cardiac edema or tail curvature in wild-type embryos, as well as in ar mutants, suggesting AR-independent pathways. We then mutated putative membrane androgen receptors [gprc6a, hcar1-4 and zip9 (slc39a9)] and found that only gprc6a mutants …

Anti-Programmed Death Ligand 1 Plus Targeted Therapy In Anaplastic Thyroid Carcinoma: A Nonrandomized Clinical Trial, Maria E Cabanillas, Ramona Dadu, Renata Ferrarotto, Maria Gule-Monroe, Suyu Liu, Bryan Fellman, Michelle D Williams, Mark Zafereo, Jennifer R Wang, Charles Lu, Matthew Ning, Brian A Mckinley, Scott E Woodman, Dzifa Duose, Gary B Gunn, Naifa L Busaidy, Rare Tumor Initiative Team

Faculty, Staff and Student Publications

Importance: Anaplastic thyroid carcinoma (ATC) is a rare and lethal cancer. Although progress has been made in recent years in patients with mutated BRAF tumors, those who respond initially eventually die of their disease; furthermore, there are no approved therapies for non-BRAF mutated tumors.

Objective: To determine whether treatment with matched-targeted therapy plus immune checkpoint inhibitors were associated with improved overall survival (OS).

Design, setting, and participants: A phase 2 trial at a single center, tertiary institution with parallel cohorts, assigning treatment with targeted therapy according to the tumor mutation status. Patients with mutated BRAF V600E tumors received vemurafenib/cobimetinib plus …

Evaluating Novel In Silico Tools For Accurate Pathogenicity Classification In Epilepsy-Associated Genetic Missense Variants, Ludovica Montanucci, Tobias Brünger, Christian M Boßelmann, Alina Ivaniuk, Eduardo Pérez-Palma, Samden Lhatoo, Costin Leu, Dennis Lal

Faculty, Staff and Student Publications

Objective: Determining the pathogenicity of missense variants in clinical genetic tests for individuals with epilepsy is crucial for guiding personalized treatment. However, achieving a definitive pathogenic classification remains challenging, with most missense variants still classified as variants of uncertain significance (VUS) and with the availability of many computational tools which may provide conflicting predictions. Here, we aim to evaluate the performance of state-of-the-art computational tools in pathogenicity prediction of missense variants in epilepsy-associated genes. This will assist in selecting the most appropriate tool and critically assess their use in clinical setting.

Methods: We assessed the performance of nine in silico …

Ras-Mutant Leukaemia Stem Cells Drive Clinical Resistance To Venetoclax, Junya Sango, Saul Carcamo, Maria Sirenko, Abhishek Maiti, Hager Mansour, Gulay Ulukaya, Lewis E Tomalin, Nataly Cruz-Rodriguez, Tiansu Wang, Malgorzata Olszewska, Emmanuel Olivier, Manon Jaud, Bettina Nadorp, Benjamin Kroger, Feng Hu, Lewis Silverman, Stephen S Chung, Elvin Wagenblast, Ronan Chaligne, Ann-Kathrin Eisfeld, Deniz Demircioglu, Dan A Landau, Piro Lito, Elli Papaemmanuil, Courtney D Dinardo, Dan Hasson, Marina Konopleva, Eirini P Papapetrou

Faculty, Staff and Student Publications

Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukaemia, upon progression or relapsed/refractory disease1-6. Here, by using human leukaemogenesis models, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors) harbouring previously acquired driver mutations, showing that advanced leukaemic clones can originate from a different cell type …

Sitravatinib In Patients With Solid Tumors Selected By Molecular Alterations: Results From A Phase Ib Study, Lyudmila Bazhenova, Dong-Wan Kim, Byoung Chul Cho, Sanjay Goel, Rebecca Heist, Theresa L Werner, Keith D Eaton, Judy S Wang, Shubham Pant, Douglas R Adkins, Collin M Blakely, Xiaohong Yan, Saskia Neuteboom, James G Christensen, Richard Chao, Todd Bauer

Faculty, Staff and Student Publications

No abstract provided.

Cadasil: A Notch3-Associated Cerebral Small Vessel Disease, Lamei Yuan, Xiangyu Chen, Joseph Jankovic, Hao Deng

Faculty, Staff and Students Publications

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD), pathologically characterized by a non-atherosclerotic and non-amyloid diffuse angiopathy primarily involving small to medium-sized penetrating arteries and leptomeningeal arteries. In 1996, mutation in the notch receptor 3 gene (NOTCH3) was identified as the cause of CADASIL. However, since that time other genetic CSVDs have been described, including the HtrA serine peptidase 1 gene-associated CSVD and the cathepsin A gene-associated CSVD, that clinically mimic the original phenotype. Though NOTCH3-associated CSVD is now a well-recognized hereditary disorder and the number of …

Clc-Kb Pore Mutation Disrupts Glycosylation And Triggers Distal Tubular Remodeling, Yogita Sharma, Robin Lo, Viktor N Tomilin, Kotdaji Ha, Holly Deremo, Aishwarya V Pareek, Wuxing Dong, Xiaohui Liao, Svetlana Lebedeva, Vivek Charu, Neeraja Kambham, Kerim Mutig, Oleh Pochynyuk, Vivek Bhalla

Faculty, Staff and Student Publications

Mutations in the CLCNKB gene (1p36), encoding the basolateral chloride channel ClC-Kb, cause type 3 Bartter syndrome. We identified a family with a mixed Bartter/Gitelman phenotype and early-onset kidney failure and by employing a candidate gene approach, identified what we believe is a novel homozygous mutation (CLCNKB c.499G>T [p.Gly167Cys]) in exon 6 of CLCNKB in the index patient. We then validated these results with Sanger and whole-exome sequencing. Compared with wild-type ClC-Kb, the Gly167Cys mutant conducted less current and exhibited impaired complex N-linked glycosylation in vitro. We demonstrated that loss of Gly-167, rather than gain of a mutant Cys, …

Genetic Risk Stratification And Outcomes Among Treatment-Naive Patients With Aml Treated With Venetoclax And Azacitidine, Hartmut Döhner, Keith W Pratz, Courtney D Dinardo, Andrew H Wei, Brian A Jonas, Vinod A Pullarkat, Michael J Thirman, Christian Récher, Andre C Schuh, Sunil Babu, Xiaotong Li, Grace Ku, Zihuan Liu, Yan Sun, Jalaja Potluri, Monique Dail, Brenda Chyla, Daniel A Pollyea

Faculty, Staff and Student Publications

The European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems are based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. This pooled analysis of the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to the 2017 and 2022 ELN risk classifications and derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on overall survival (OS). Overall, 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. The ELN 2017 or 2022 prognostic criteria classified most …

Epigenome Reprogramming Through H3k27 And H3k4 Trimethylation As A Resistance Mechanism To Dna Methylation Inhibition In Brafv600e-Mutated Colorectal Cancer, Hey Min Lee, Ajay Kumar Saw, Van K Morris, Stefania Napolitano, Christopher Bristow, Sanjana Srinivasan, Micheal Peoples, Alexey Sorokin, Preeti Kanikarla Marie, Jonathan Schulz, Anand K Singh, Christopher Terranova, Oluwadara Coker, Abhinav Jain, Scott Kopetz, Kunal Rai

Faculty, Staff and Student Publications

Purpose: BRAFV600E-mutated colorectal cancer exhibits a strong correlation with DNA hypermethylation, suggesting that this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E colorectal cancer in vivo.

Experimental design: We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E colorectal cancer models.

Results: A profound reduction of DNA …

Outcomes Of Patients With Acute Myeloid Leukemia And Bone Marrow Fibrosis, Samuel Urrutia, Hagop M Kantarjian, Farhad Ravandi-Kashani, Carlos Bueso-Ramos, Rashmi Kanagal-Shamanna, Elias Jabbour, Guillermo Montalban-Bravo, Nicholas J Short, Naval Daver, Gautam Borthakur, Courtney D Dinardo, Tapan M Kadia, Lucia Masarova, Prithviraj Bose, Naveen Pemmaraju, Guillermo Garcia-Manero, Koji Sasaki

Faculty, Staff and Student Publications

The outcomes of patients with acute myeloid leukemia (AML) and bone marrow fibrosis (MF) are not well defined. The study objectives were to evaluate the degrees of MF in AML, and corresponding response rates and outcomes. We performed a retrospective review of 2302 patients with AML. We annotated the clinical and molecular characteristics, response to therapy, and survival outcomes of patients with bone marrow fibrosis. Overall, 492 patients (21.4%) had a reported microscopic evaluation of MF: 344 (69.9%) had MF grade 0-1 and 148 (30.1%) had MF grade 2-3. Patients with MF 2-3 had a higher proportion of complex cytogenetics …

Evidence That Crispr-Cas9 Y537s-Mutant Expressing Breast Cancer Cells Activate Yes-Associated Protein 1 To Driving The Conversion Of Normal Fibroblasts Into Cancer-Associated Fibroblasts, Luca Gelsomino, Amanda Caruso, Emine Tasan, Adele Elisabetta Leonetti, Rocco Malivindi, Giuseppina Daniela Naimo, Francesca Giordano, Salvatore Panza, Guowei Gu, Benedetta Perrone, Cinzia Giordano, Loredana Mauro, Bruno Nardo, Gianfranco Filippelli, Daniela Bonofiglio, Ines Barone, Suzanne A W Fuqua, Stefania Catalano, Sebastiano Andò

Faculty, Staff and Students Publications

BACKGROUND: Endocrine therapy (ET) has improved the clinical outcomes of Estrogen receptor alpha-positive (ERɑ +) breast cancer (BC) patients, even though resistance to ET remains a clinical issue. Mutations in the hormone-binding domain of ERɑ represent an acquired intrinsic mechanism of ET resistance. However, the latter also depends on the multiple functional interactions between BC cells and the tumor microenvironment (TME). Here, we investigated how the most common Y537S-ERɑ mutation may influence the behavior of fibroblasts, the most prominent component of the TME.

METHODS: We conducted coculture experiments with normal human foreskin fibroblasts BJ1-hTERT (NFs), cancer-associated fibroblasts (CAFs), isolated from …

Homozygous Variants In Wdr83os Lead To A Neurodevelopmental Disorder With Hypercholanemia, Scott Barish, Sheng-Jia Lin, Reza Maroofian, Alper Gezdirici, Hamoud Alhebby, Aurélien Trimouille, Marta Biderman Waberski, Tadahiro Mitani, Ilka Huber, Kristian Tveten, Øystein L Holla, Øyvind L Busk, Henry Houlden, Ehsan Ghayoor Karimiani, Mehran Beiraghi Toosi, Reza Shervin Badv, Paria Najarzadeh Torbati, Fatemeh Eghbal, Javad Akhondian, Ayat Al Safar, Abdulrahman Alswaid, Giovanni Zifarelli, Peter Bauer, Dana Marafi, Jawid M Fatih, Kevin Huang, Cassidy Petree, Daniel G Calame, Charlotte Von Der Lippe, Fowzan S Alkuraya, Sami Wali, James R Lupski, Gaurav K Varshney, Jennifer E Posey, Davut Pehlivan

Faculty, Staff and Students Publications

WD repeat domain 83 opposite strand (WDR83OS) encodes the 106-aa (amino acid) protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex. This complex functions as a chaperone for large proteins containing transmembrane domains to ensure proper folding. Until recently, little was known about the role of WDR83OS or CCDC47 in human disease traits. However, biallelic variants in CCDC47 were identified in four unrelated families with trichohepatoneurodevelopmental syndrome, characterized by a neurodevelopmental disorder (NDD) with liver dysfunction. Three affected siblings in an additional family share a homozygous truncating WDR83OS variant and a phenotype of …

Estimating The Number Of Polygenic Diseases Among Six Mutually Exclusive Entities Of Non-Tumors And Cancer, C I Edvard Smith, Jan A Burger, Rula Zain

Faculty, Staff and Student Publications

In the era of precision medicine with increasing amounts of sequenced cancer and non-cancer genomes of different ancestries, we here enumerate the resulting polygenic disease entities. Based on the cell number status, we first identified six fundamental types of polygenic illnesses, five of which are non-cancerous. Like complex, non-tumor disorders, neoplasms normally carry alterations in multiple genes, including in 'Drivers' and 'Passengers'. However, tumors also lack certain genetic alterations/epigenetic changes, recently named 'Goners', which are toxic for the neoplasm and potentially constitute therapeutic targets. Drivers are considered essential for malignant transformation, whereas environmental influences vary considerably among both types of …

Characterization Of Driver Mutations Identifies Gene Signatures Predictive Of Prognosis And Treatment Sensitivity In Multiple Myeloma, Jian-Rong Li, Abinand Krishna Parthasarathy, Aravind Singaram Kannappan, Shahram Arsang-Jang, Jing Dong, Chao Cheng

Faculty, Staff and Students Publications

In multiple myeloma (MM), while frequent mutations in driver genes are crucial for disease progression, they traditionally offer limited insights into patient prognosis. This study aims to enhance prognostic understanding in MM by analyzing pathway dysregulations in key cancer driver genes, thereby identifying actionable gene signatures. We conducted a detailed quantification of mutations and pathway dysregulations in 10 frequently mutated cancer driver genes in MM to characterize their comprehensive mutational impacts on the whole transcriptome. This was followed by a systematic survival analysis to identify significant gene signatures with enhanced prognostic value. Our systematic analysis highlighted 2 significant signatures, TP53 …

Outcomes And Genetic Dynamics Of Acute Myeloid Leukemia At First Relapse, Alex Bataller, Hagop Kantarjian, Alexandre Bazinet, Tapan Kadia, Naval Daver, Courtney D Dinardo, Gautam Borthakur, Sanam Loghavi, Keyur Patel, Guilin Tang, Koji Sasaki, Nicholas J Short, Musa Yilmaz, Ghayas C Issa, Yesid Alvarado, Guillermo Montalban-Bravo, Abhishek Maiti, Hussein A Abbas, Koichi Takahashi, Sherry Pierce, Elias Jabbour, Guillermo Garcia-Manero, Farhad Ravandi

Faculty, Staff and Student Publications

Patients with relapsed acute myeloid leukemia (AML) experience dismal outcomes. We performed a comprehensive analysis of patients with relapsed AML to determine the genetic dynamics and factors predicting survival. We analyzed 875 patients with newly diagnosed AML who received intensive treatment or low-intensity treatment. Of these patients, 197 subsequently relapsed. Data were available for 164 of these patients, with a median time from complete remission/complete remission with incomplete blood count recovery to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation. At relapse, mutations in genes involved in pathway signaling tended …

Cohort Expansion And Genotype-Phenotype Analysis Of Rab11a-Associated Neurodevelopmental Disorder, Maria Carla Borroto, Heena Patel, Siddharth Srivastava, Lindsay C Swanson, Boris Keren, Sandra Whalen, Cyril Mignot, Xiaodong Wang, Qian Chen, Jill A Rosenfeld, Scott Mclean, Rebecca O Littlejohn, Undiagnosed Diseases Network, Lisa Emrick, Lindsay C Burrage, Ruben Attali, Gaetan Lesca, Cecile Acquaviva-Bourdain, Catherine Sarret, Laurie H Seaver, Konrad Platzer, Tobias Bartolomaeus, Cornelia Wünsch, Susann Fischer, Ana Maria Rodriguez Barreto, Jorge L Granadillo, Elisabeth Schreiner, Theresa Brunet, Ulrich A Schatz, Isabelle Thiffault, Sureni V Mullegama, Jacques L Michaud, Fadi F Hamdan, Elsa Rossignol, Philippe M Campeau

Faculty, Staff and Students Publications

Background: GTPases of the Rab family are important orchestrators of membrane trafficking, and their dysregulation has been linked to a variety of neuropathologies. In 2017, we established a causal link between RAB11A variants and developmental and epileptic encephalopathy. In this study, we expand the phenotype of RAB11A-associated neurodevelopmental disorder and explore genotype-phenotype correlations.

Methods: We assessed 16 patients with pathogenic or likely pathogenic RAB11A variants, generally de novo, heterozygous missense variants. One individual had a homozygous nonsense variant, although concomitant with a pathogenic LAMA2 variant, which made their respective contributions to the phenotype difficult to discriminate.

Results: We reinforce the …

Mechanisms Of Resistance To Oncogenic Kras Inhibition In Pancreatic Cancer, Julien Dilly, Megan T Hoffman, Laleh Abbassi, Ziyue Li, Francesca Paradiso, Brendan D Parent, Connor J Hennessey, Alexander C Jordan, Micaela Morgado, Shatavisha Dasgupta, Giselle A Uribe, Annan Yang, Kevin S Kapner, Felix P Hambitzer, Li Qiang, Hanrong Feng, Jacob Geisberg, Junning Wang, Kyle E Evans, Hengyu Lyu, Aislyn Schalck, Ningping Feng, Anastasia M Lopez, Christopher A Bristow, Michael P Kim, Kimal I Rajapakshe, Vahid Bahrambeigi, Jennifer A Roth, Kavita Garg, Paola A Guerrero, Ben Z Stanger, Simona Cristea, Scott W Lowe, Timour Baslan, Eliezer M Van Allen, Joseph D Mancias, Emily Chan, Abraham Anderson, Yuliya V Katlinskaya, Alex K Shalek, David S Hong, Shubham Pant, Jill Hallin, Kenna Anderes, Peter Olson, Timothy P Heffernan, Seema Chugh, James G Christensen, Anirban Maitra, Brian M Wolpin, Srivatsan Raghavan, Jonathan A Nowak, Peter S Winter, Stephanie K Dougan, Andrew J Aguirre

Faculty, Staff and Student Publications

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, Cdk6, and Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. …

Hu8f4-Car T Cells With Mutated Fc Spacer Segment Improve Target Specificity And Mediate Anti-Leukemia Activity In Vivo, Hong He, Rolando A Vedia, Sijie Lu, Qiaochuan Li, Kathryn R Cox, Lisa St John, Anna Sergeeva, Karen Clise-Dwyer, Gheath Alatrash, Elizabeth J Shpall, Qing Ma, Jeffrey J Molldrem

Faculty, Staff and Student Publications

Background aims: Hu8F4 is a T-cell receptor-like antibody with high affinity for the leukemia-associated antigen PR1/HLA-A2 epitope. Adapted into a chimeric antigen receptor (CAR) format, Hu8F4-CAR is composed of the Hu8F4 single-chain variable fragment, the human IgG1 CH2CH3 extracellular spacer domain, a human CD28 costimulatory domain and the human CD3ζ signaling domain. We have demonstrated high efficacy of Hu8F4-CAR-T cells against PR1/HLA-A2-expressing cell lines and leukemic blasts from patients with acute myeloid leukemia in vitro. Previous studies have shown that modification of the Fc domains of IgG4 CH2CH3 spacer regions can eliminate activation-induced cell death and off-target killing mediated by …

Genomic Alterations In Dna Mismatch Repair Genes Across Different Cancer Types, Vijaykumar R Holla, Michael P Kahle, Sun-Hee Kim, Arash Ronaghy, Richard K Yang, Keyur P Patel, Mark J Routbort, Michael J Overman, Ecaterina E Dumbrava, Kenna R Mills Shaw, Daniel D Karp, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Purpose: PD-1 inhibition is effective in patients with mismatch repair deficient (dMMR) solid tumors in a tumor-agnostic fashion. However, dMMR testing by immunohistochemistry (IHC) is not routinely performed across tumor types. By contrast, next-generation sequencing (NGS) for somatic genomic alterations is frequently performed across tumor types. We hypothesized that NGS would identify patients with alterations in mismatch repair (MMR) genes and that these patients would have higher rates of MMR protein loss by IHC. This would support the utility of IHC reflex testing after NGS and potential matching to approved therapeutic options.

Methods: From January 2016 to December 2021, 15,701 …

Molecular Profiling Of Braf-V600e-Mutant Metastatic Colorectal Cancer In The Phase 3 Beacon Crc Trial, Scott Kopetz, Danielle A Murphy, Jie Pu, Fortunato Ciardiello, Jayesh Desai, Eric Van Cutsem, Harpreet Singh Wasan, Takayuki Yoshino, Hedieh Saffari, Xiaosong Zhang, Phineas Hamilton, Tao Xie, Rona Yaeger, Josep Tabernero

Faculty, Staff and Student Publications

The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)±binimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. A greater understanding of biomarkers predictive of response to Enco+Cetux±Bini treatment is of clinical relevance. In this prespecified, exploratory biomarker analysis of the BEACON CRC study, we characterize genomic and transcriptomic correlates of clinical outcomes and acquired resistance mechanisms through integrated clinical and molecular analysis, including whole-exome and -transcriptome tissue sequencing and circulating tumor DNA genomic …

Ctla4 Blockade Abrogates Keap1/Stk11-Related Resistance To Pd-(L)1 Inhibitors, Ferdinandos Skoulidis, Haniel A Araujo, Minh Truong Do, Yu Qian, Xin Sun, Ana Galan Cobo, John T Le, Meagan Montesion, Rachael Palmer, Nadine Jahchan, Joseph M Juan, Chengyin Min, Yi Yu, Xuewen Pan, Kathryn C Arbour, Natalie Vokes, Stephanie T Schmidt, David Molkentine, Dwight H Owen, Regan Memmott, Pradnya D Patil, Melina E Marmarelis, Mark M Awad, Joseph C Murray, Jessica A Hellyer, Justin F Gainor, Anastasios Dimou, Christine M Bestvina, Catherine A Shu, Jonathan W Riess, Collin M Blakely, Chad V Pecot, Laura Mezquita, Fabrizio Tabbó, Matthias Scheffler, Subba Digumarthy, Meghan J Mooradian, Adrian G Sacher, Sally C M Lau, Andreas N Saltos, Julia Rotow, Rocio Perez Johnson, Corinne Liu, Tyler Stewart, Sarah B Goldberg, Jonathan Killam, Zenta Walther, Kurt Schalper, Kurtis D Davies, Mark G Woodcock, Valsamo Anagnostou, Kristen A Marrone, Patrick M Forde, Biagio Ricciuti, Deepti Venkatraman, Eliezer M Van Allen, Amy L Cummings, Jonathan W Goldman, Hiram Shaish, Melanie Kier, Sharyn Katz, Charu Aggarwal, Ying Ni, Joseph T Azok, Jeremy Segal, Lauren Ritterhouse, Joel W Neal, Ludovic Lacroix, Yasir Y Elamin, Marcelo V Negrao, Xiuning Le, Vincent K Lam, Whitney E Lewis, Haley N Kemp, Brett Carter, Jack A Roth, Stephen Swisher, Richard Lee, Teng Zhou, Alissa Poteete, Yifan Kong, Tomohiro Takehara, Alvaro Guimaraes Paula, Edwin R Parra Cuentas, Carmen Behrens, Ignacio I Wistuba, Jianjun Zhang, George R Blumenschein, Carl Gay, Lauren A Byers, Don L Gibbons, Anne Tsao, J Jack Lee, Trever G Bivona, D Ross Camidge, Jhannelle E Gray, Natasha B Leighl, Benjamin Levy, Julie R Brahmer, Marina C Garassino, David R Gandara, Edward B Garon, Naiyer A Rizvi, Giorgio Vittorio Scagliotti, Jürgen Wolf, David Planchard, Benjamin Besse, Roy S Herbst, Heather A Wakelee, Nathan A Pennell, Alice T Shaw, Pasi A Jänne, David P Carbone, Matthew D Hellmann, Charles M Rudin, Lee Albacker, Helen Mann, Zhou Zhu, Zhongwu Lai, Ross Stewart, Solange Peters, Melissa L Johnson, Kwok K Wong, Alan Huang, Monte M Winslow, Michael J Rosen, Ian P Winters, Vassiliki A Papadimitrakopoulou, Tina Cascone, Philip Jewsbury, John V Heymach

Faculty, Staff and Student Publications

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added …