Medical Genetics Commons^™

Variant-Specific Pathophysiological Mechanisms Of Aff3 Differently Influence Transcriptome Profiles, Sissy Bassani, Jacqueline Chrast, Giovanna Ambrosini, Norine Voisin, Frédéric Schütz, Alfredo Brusco, Fabio Sirchia, Lydia Turban, Susanna Schubert, Rami Abou Jamra, Jan-Ulrich Schlump, Desiree Demille, Pinar Bayrak-Toydemir, Gary Rex Nelson, Kristen Nicole Wong, Laura Duncan, Mackenzie Mosera, Christian Gilissen, Lisenka E L M Vissers, Rolph Pfundt, Rogier Kersseboom, Hilde Yttervik, Geir Åsmund Myge Hansen, Marie Falkenberg Smeland, Kameryn M Butler, Michael J Lyons, Claudia M B Carvalho, Chaofan Zhang, James R Lupski, Lorraine Potocki, Leticia Flores-Gallegos, Rodrigo Morales-Toquero, Florence Petit, Binnaz Yalcin, Annabelle Tuttle, Houda Zghal Elloumi, Lane Mccormick, Mary Kukolich, Oliver Klaas, Judit Horvath, Marcello Scala, Michele Iacomino, Francesca Operto, Federico Zara, Karin Writzl, Aleš Maver, Maria K Haanpää, Pia Pohjola, Harri Arikka, Anneke J A Kievit, Camilla Calandrini, Christian Iseli, Nicolas Guex, Alexandre Reymond

Faculty, Staff and Students Publications

BACKGROUND: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.

METHODS: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.

RESULTS: We identified …

Differentiation Syndrome Associated With Treatment With Idh2 Inhibitor Enasidenib: Pooled Analysis From Clinical Trials, Pau Montesinos, Amir T Fathi, Stéphane De Botton, Eytan M Stein, Amer M Zeidan, Yue Zhu, Thomas Prebet, Carlos E Vigil, Iryna Bluemmert, Xin Yu, Courtney D Dinardo

Faculty, Staff and Student Publications

Treatment with enasidenib, a selective mutant isocitrate dehydrogenase isoform 2 (IDH2) inhibitor, has been associated with the development of differentiation syndrome (DS) in patients with acute myeloid leukemia (AML). Studies on the incidence and clinical features of DS are limited in this setting, and diagnosis is challenging because of nonspecific symptoms. This study assessed the incidence, diagnostic criteria, risk factors, and correlation with clinical response of DS based on the pooled analysis of 4 clinical trials in patients with IDH2-mutated AML treated with enasidenib as monotherapy, or in combination with azacitidine or with chemotherapy. Across the total AML population, 67 …

Accelerated Somatic Mutation Calling For Whole-Genome And Whole-Exome Sequencing Data From Heterogenous Tumor Samples, Shuangxi Ji, Tong Zhu, Ankit Sethia, Wenyi Wang

Faculty, Staff and Student Publications

Accurate detection of somatic mutations in DNA sequencing data is a fundamental prerequisite for cancer research. Previous analytical challenges were overcome by consensus mutation calling from four to five popular callers. This, however, increases the already nontrivial computing time from individual callers. Here, we launch MuSE 2, powered by multistep parallelization and efficient memory allocation, to resolve the computing time bottleneck. MuSE 2 speeds up 50 times more than MuSE 1 and eight to 80 times more than other popular callers. Our benchmark study suggests combining MuSE 2 and the recently accelerated Strelka2 achieves high efficiency and accuracy in analyzing …

The Greenbeard Gene Tgrb1 Regulates Altruism And Cheating In Dictyostelium Discoideum, Mariko Katoh-Kurasawa, Peter Lehmann, Gad Shaulsky

Faculty, Staff and Students Publications

Greenbeard genetic elements encode rare perceptible signals, signal recognition ability, and altruism towards others that display the same signal. Putative greenbeards have been described in various organisms but direct evidence for all the properties in one system is scarce. The tgrB1-tgrC1 allorecognition system of Dictyostelium discoideum encodes two polymorphic membrane proteins which protect cells from chimerism-associated perils. During development, TgrC1 functions as a ligand-signal and TgrB1 as its receptor, but evidence for altruism has been indirect. Here, we show that mixing wild-type and activated tgrB1 cells increases wild-type spore production and relegates the mutants to the altruistic stalk, whereas mixing …

Imaging Features Of Primary Intracranial Sarcoma With Dicer1 Mutation: A Multicenter Case Series, Rami W Eldaya, Richard J Fagan, Samir A Dagher, Angshumoy Roy, Sonika Dahyia, Gregory N Fuller, Max Wintermark, Matthew S Parsons, Thierry A G M Huisman

Faculty, Staff and Student Publications

Primary intracranial sarcoma, DICER1-mutant, is a rare, recently described entity in the fifth edition of the WHO Classification of CNS Tumors. Given the entity's rarity and recent description, imaging data on primary intracranial sarcoma, DICER1-mutant, remains scarce. In this multicenter case series, we present detailed multimodality imaging features of primary intracranial sarcoma, DICER1-mutant, with emphasis on the appearance of the entity on MR imaging. In total, 8 patients were included. In all 8 patients, the lesion demonstrated blood products on T1WI. In 7 patients, susceptibility-weighted imaging was obtained and demonstrated blood products. Primary intracranial sarcoma, DICER1-mutant, …

Exome Sequencing Implicates Ancestry-Related Mendelian Variation At Syne1 In Childhood-Onset Essential Hypertension, Ian Copeland, Edmond Wonkam-Tingang, Monesha Gupta-Malhotra, S Shahrukh Hashmi, Yixing Han, Aarti Jajoo, Nancy J Hall, Paula P Hernandez, Natasha Lie, Dan Liu, Jun Xu, Jill Rosenfeld, Aparna Haldipur, Zelene Desire, Zeynep H Coban-Akdemir, Daryl A Scott, Qing Li, Hsiao-Tuan Chao, Ana M Zaske, James R Lupski, Dianna M Milewicz, Sanjay Shete, Jennifer E Posey, Neil A Hanchard

Faculty, Staff and Student Publications

Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date. Here, we identify recessive segregation of rare and putatively damaging missense variation in the spectrin domain of spectrin repeat containing nuclear envelope …

Targeted Accurate Rna Consensus Sequencing (Tarc-Seq) Reveals Mechanisms Of Replication Error Affecting Sars-Cov-2 Divergence, Catherine C Bradley, Chen Wang, Alasdair J E Gordon, Alice X Wen, Pamela N Luna, Matthew B Cooke, Brendan F Kohrn, Scott R Kennedy, Vasanthi Avadhanula, Pedro A Piedra, Olivier Lichtarge, Chad A Shaw, Shannon E Ronca, Christophe Herman

Duncan NRI Faculty and Staff Publications

RNA viruses, like SARS-CoV-2, depend on their RNA-dependent RNA polymerases (RdRp) for replication, which is error-prone. Monitoring replication errors is crucial for understanding the virus’s evolution. Current methods lack the precision to detect rare de novo RNA mutations, particularly in low-input samples such as those from patients. Here, we introduce a new targeted Accurate RNA Consensus sequencing method (tARC-seq) to accurately determine the mutation frequency and types in SARS-CoV-2, both in cell culture and clinical samples. Our findings show an average of 2.68×10−5 new errors per cycle with a C>T bias that cannot be solely attributed to APOBEC …

Somatic Gene Mutation Patterns And Burden Influence Outcomes With Enasidenib In Relapsed/Refractory Idh2-Mutated Aml, Alberto Risueño, Wendy L See, Iryna Bluemmert, Stéphane De Botton, Courtney D Dinardo, Amir T Fathi, Andre C Schuh, Pau Montesinos, Paresh Vyas, Thomas Prebet, Anita Gandhi, Maroof Hasan

Faculty, Staff and Student Publications

Limited treatment options are available for patients with relapsed/refractory acute myeloid leukemia (R/R AML). We recently reported results from the phase 3 IDHENTIFY trial (NCT02577406) showing improved response rates and event-free survival with enasidenib monotherapy compared with conventional care regimens (CCR) in heavily pretreated, older patients with late-stage R/R AML bearing IDH2 mutations. Here we investigated the prognostic impact of mutational burden and different co-mutation patterns at study entry within the predominant IDH2 variant subclasses, IDH2-R140 and IDH2-R172. The prognostic relevance of these variants is well documented in newly diagnosed AML, but data are lacking in R/R AML. In this …

Azacitidine, Venetoclax, And Gilteritinib In Newly Diagnosed And Relapsed Or Refractory Flt3-Mutated Aml, Nicholas J Short, Naval Daver, Courtney D Dinardo, Tapan Kadia, Lewis F Nasr, Walid Macaron, Musa Yilmaz, Gautam Borthakur, Guillermo Montalban-Bravo, Guillermo Garcia-Manero, Ghayas C Issa, Kelly S Chien, Elias Jabbour, Cedric Nasnas, Xuelin Huang, Wei Qiao, Jairo Matthews, Christopher J Stojanik, Keyur P Patel, Regina Abramova, Jennifer Thankachan, Marina Konopleva, Hagop Kantarjian, Farhad Ravandi

Faculty, Staff and Student Publications

Purpose: Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML.

Methods: This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3-mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose …

Genomic Landscape Of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens For Immunoprevention, Ana M Bolivar, Fahriye Duzagac, Nan Deng, Laura Reyes-Uribe, Kyle Chang, Wenhui Wu, Charles M Bowen, Melissa W Taggart, Selvi Thirumurthi, Patrick M Lynch, Y Nancy You, Jesus Rodriguez-Pascual, Steven M Lipkin, Scott Kopetz, Paul Scheet, Gregory A Lizee, Alexandre Reuben, Krishna M Sinha, Eduardo Vilar

Faculty, Staff and Student Publications

Background & aims: Lynch syndrome (LS) carriers develop mismatch repair-deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers in LS carriers.

Methods: We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 …

Mapping Genotypes To Chromatin Accessibility Profiles In Single Cells, Franco Izzo, Robert M Myers, Saravanan Ganesan, Levan Mekerishvili, Sanjay Kottapalli, Tamara Prieto, Elliot O Eton, Theo Botella, Andrew J Dunbar, Robert L Bowman, Jesus Sotelo, Catherine Potenski, Eleni P Mimitou, Maximilian Stahl, Sebastian El Ghaity-Beckley, Joann Arandela, Ramya Raviram, Daniel C Choi, Ronald Hoffman, Ronan Chaligné, Omar Abdel-Wahab, Peter Smibert, Irene M Ghobrial, Joseph M Scandura, Bridget Marcellino, Ross L Levine, Dan A Landau

Faculty, Staff and Student Publications

In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. …

Survival Outcomes Of Patients With Her2/Neu-Positive Breast Cancer With Germline Brca Mutations, Fatma Nihan Akkoc Mustafayev, Mihir Amitabh Shukla, Amanda Lanier, Denái R Milton, Angelica M Gutierrez, Stephen K Gruschkus, John E Lewis, Rashmi K Murthy, Banu K Arun

Faculty, Staff and Student Publications

Background: Breast cancer (BC) with germline BRCA1/2 mutations and their association with triple-negative BC has been thoroughly investigated. However, some carriers of BRCA1/2 mutations have human epidermal growth factor receptor 2 (HER2/neu)-positive BC, which has a different targeted therapy approach, and data are scarce for this patient population. The authors sought to characterize the clinical characteristics and outcomes of patients with HER2/neu-positive BC who had germline BRCA1/2 mutations.

Methods: This was a retrospective analysis of data from 1099 patients diagnosed with HER2/neu-positive BC who were screened for germline BRCA mutations between 1996 and 2022. Clinicopathologic features and survival rates were …

Human Dna Polymerase Θ Does Not Harbor Intrinsic Nuclease Activity, Denisse Carvajal-Maldonado, Karl Zahn, Ryan Jensen, Richard D Wood, Sylvie Doublié

Faculty, Staff and Student Publications

No abstract provided.

Somatic Mutations Of Esophageal Adenocarcinoma: A Comparison Between Black And White Patients, Hyeyeun Lim, Marie-Claude Gingras, Jing Zhao, Jinyoung Byun, Patricia D Castro, Spiridon Tsavachidis, Jianhong Hu, Harshavardhan Doddapaneni, Yi Han, Donna M Muzny, Richard A Gibbs, Christopher I Amos, Aaron P Thrift

Faculty, Staff and Students Publications

Esophageal adenocarcinoma is the most common histological subtype of esophageal cancer in Western countries and shows poor prognosis with rapid growth. EAC is characterized by a strong male predominance and racial disparity. EAC is up to fivefold more common among Whites than Blacks, yet Black patients with EAC have poorer survival rates. The racial disparity remains largely unknown, and there is limited knowledge of mutations in EAC regarding racial disparities. We used whole-exome sequencing to show somatic mutation profiles derived from tumor samples from 18 EAC male patients. We identified three molecular subgroups based on the pre-defined esophageal cancer-specific mutational …

Nivolumab Plus Chemotherapy In Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression On Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results Of Checkmate 722, Tony Mok, Kazuhiko Nakagawa, Keunchil Park, Yuichiro Ohe, Nicolas Girard, Hye Ryun Kim, Yi-Long Wu, Justin Gainor, Se-Hoon Lee, Chao-Hua Chiu, Sang-We Kim, Cheng-Ta Yang, Chien Liang Wu, Lin Wu, Meng-Chih Lin, Jens Samol, Kazuya Ichikado, Mengzhao Wang, Xiaoqing Zhang, Judi Sylvester, Sunney Li, Ann Forslund, James Chih-Hsin Yang

Faculty, Staff and Student Publications

PURPOSE: The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor (

METHODS: Patients with disease progression after first- or second-generation EGFR TKI therapy (without

RESULTS: Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6

CONCLUSION: Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with

Arid1a Orchestrates Swi/Snf-Mediated Sequential Binding Of Transcription Factors With Arid1a Loss Driving Pre-Memory B Cell Fate And Lymphomagenesis, Darko Barisic, Christopher R Chin, Cem Meydan, Matt Teater, Ioanna Tsialta, Coraline Mlynarczyk, Amy Chadburn, Xuehai Wang, Margot Sarkozy, Min Xia, Sandra E Carson, Santo Raggiri, Sonia Debek, Benedikt Pelzer, Ceyda Durmaz, Qing Deng, Priya Lakra, Martin Rivas, Christian Steidl, David W Scott, Andrew P Weng, Christopher E Mason, Michael R Green, Ari Melnick

Faculty, Staff and Student Publications

ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with …

De Novo Variants In Fryl Are Associated With Developmental Delay, Intellectual Disability, And Dysmorphic Features, Xueyang Pan, Alice M Tao, Shenzhao Lu, Mengqi Ma, Shabab B Hannan, Rachel Slaugh, Sarah Drewes Williams, Lauren O'Grady, Oguz Kanca, Richard Person, Melissa T Carter, Konrad Platzer, Franziska Schnabel, Rami Abou Jamra, Amy E Roberts, Jane W Newburger, Anya Revah-Politi, Jorge L Granadillo, Alexander P A Stegmann, Margje Sinnema, Andrea Accogli, Vincenzo Salpietro, Valeria Capra, Lina Ghaloul-Gonzalez, Martina Brueckner, Marleen E H Simon, David A Sweetser, Kevin E Glinton, Susan E Kirk, Baylor College Of Medicine Center For Precision Medicine Models, Michael F Wangler, Shinya Yamamoto, Wendy K Chung, Hugo J Bellen

Faculty, Staff and Students Publications

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is …

Genetic Analysis Of Hereditary Gingival Fibromatosis Associated Sos1 Missense Variants Of Uncertain Significance In Caenorhabditis Elegans, Himani Patel

Theses

Hereditary gingival fibromatosis (HGF) is a disease that can present as benign overgrowth of gingival tissue in the mouth. The overgrowth can enclose the entire mouth and teeth in severe cases or present itself in a concentrated area. Researchers have identified that mutations in the SOS1 gene can be responsible for HGF. This disease can impair basic functions related to the mouth. Eating, smiling, speaking can all be affected. Additionally, excess inflammation can cause periodontal disease because of the difficulty in maintaining proper oral health. Periodontal disease can lead to severe bone loss which can lead to complete loss of …

Samhd1 Compound Heterozygous Rare Variants Associated With Moyamoya And Mitral Valve Disease In The Absence Of Other Features Of Aicardi-Goutières Syndrome, Aamuktha R Karla, Amélie Pinard, Maura L Boerio, Dimitri Hemelsoet, Simon J Tavernier, Michel De Pauw, Elke Vereecke, Stuart Fraser, Michael J Bamshad, Dongchuan Guo, Bert Callewaert, Dianna M Milewicz

Faculty, Staff and Student Publications

Aicardi-Goutières syndrome (AGS) is an autosomal recessive inflammatory syndrome that manifests as an early-onset encephalopathy with both neurologic and extraneurologic clinical findings. AGS has been associated with pathogenic variants in nine genes: TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR, IFIH1, LSM11, and RNU7-1. Diagnosis is established by clinical findings (encephalopathy and acquired microcephaly, intellectual and physical impairments, dystonia, hepatosplenomegaly, sterile pyrexia, and/or chilblains), characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes), or the identification of pathogenic/likely pathogenic variants in the known genes. One of the genes associated with AGS, SAMHD1, has also …

Loss-Of-Function Mutation In Prmt9 Causes Abnormal Synapse Development By Dysregulation Of Rna Alternative Splicing, Lei Shen, Xiaokuang Ma, Yuanyuan Wang, Zhihao Wang, Yi Zhang, Hoang Quoc Hai Pham, Xiaoqun Tao, Yuehua Cui, Jing Wei, Dimitri Lin, Tharindumala Abeywanada, Swanand Hardikar, Levon Halabelian, Noah Smith, Taiping Chen, Dalia Barsyte-Lovejoy, Shenfeng Qiu, Yi Xing, Yanzhong Yang

Faculty, Staff and Student Publications

Protein arginine methyltransferase 9 (PRMT9) is a recently identified member of the PRMT family, yet its biological function remains largely unknown. Here, by characterizing an intellectual disability associated PRMT9 mutation (G189R) and establishing a Prmt9 conditional knockout (cKO) mouse model, we uncover an important function of PRMT9 in neuronal development. The G189R mutation abolishes PRMT9 methyltransferase activity and reduces its protein stability. Knockout of Prmt9 in hippocampal neurons causes alternative splicing of ~1900 genes, which likely accounts for the aberrant synapse development and impaired learning and memory in the Prmt9 cKO mice. Mechanistically, we discover a methylation-sensitive protein-RNA interaction between …

Early Elevations Of Ras Protein Level And Activity Are Critical For The Development Of Pdac In The Context Of Inflammation, Jianjia Ma, Fanghua Gong, Eunice Kim, James Xianxing Du, Cindy Leung, Qingchun Song, Craig D Logsdon, Yongde Luo, Xiaokun Li, Weiqin Lu

Faculty, Staff and Student Publications

The KRASG12D mutation was believed to be locked in a GTP-bound form, rendering it fully active. However, recent studies have indicated that the presence of mutant KRAS alone is insufficient; it requires additional activation through inflammatory stimuli to effectively drive the development of pancreatic ductal adenocarcinoma (PDAC). It remains unclear to what extent RAS activation occurs during the development of PDAC in the context of inflammation. Here, in a mouse model with the concurrent expression of KrasG12D/+ and inflammation mediator IKK2 in pancreatic acinar cells, we showed that, compared to KRASG12D alone, the cooperative interaction between KRASG12D and IKK2 rapidly …

Seamark: Phase Ii Study Of First-Line Encorafenib And Cetuximab Plus Pembrolizumab For Msi-H/Dmmr Brafv600e-Mutant Mcrc, Elena Elez, Scott Kopetz, Josep Tabernero, Tanios Bekaii-Saab, Julien Taieb, Takayuki Yoshino, Gulam Manji, Kathrine Fernandez, Antonello Abbattista, Xiaosong Zhang, Van K Morris

Faculty, Staff and Student Publications

Patients with both BRAF V600E mutations and microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) have poor prognosis. Currently, there are no specifically targeted first-line treatment options indicated for patients with mCRC whose tumors harbor both molecular aberrations. Pembrolizumab is a checkpoint inhibitor approved for the treatment of MSI-H/dMMR mCRC, and the BRAF inhibitor encorafenib, in combination with cetuximab, is approved for previously treated BRAF V600E-mutant mCRC. Combination of pembrolizumab with encorafenib and cetuximab may synergistically enhance antitumor activity in patients with BRAF V600E-mutant, MSI-H/dMMR mCRC. SEAMARK is a randomized phase II study comparing the efficacy of the combination …

Tp53 Mutation Is Frequent In Mantle Cell Lymphoma With Ezh2 Expression And Have Dismal Outcome When Both Are Present, Do Hwan Kim, Saima Siddiqui, Preetesh Jain, Michael Wang, Beenu Thakral, Shaoying Li, Roberto Miranda, Francisco Vega, L Jeffrey Medeiros, Chi Young Ok

Faculty, Staff and Student Publications

Enhancer of zeste homolog 2 (EZH2) expression is found in about 40% of mantle cell lymphoma (MCL) patients, which is associated with aggressive histology, high Ki-67 proliferation rate, p53 mutant pattern and inferior overall survival (OS). We conducted 11-gene (ATM, BIRC3, CCND1, KMT2C, KMT2D, NOTCH1, NOTCH2, RB1, TP53, TRAF2 and UBR5) next generation sequencing panel to shed more light on MCL with EZH2 expression (EZH2+ MCL). EZH2+ MCL more frequently harbor TP53 mutation compared to EZH2(-) MCL (41.2% vs. 19.1%, respectively, p = 0.045). TP53 mutation and EZH2 expression demonstrated overlapping features including aggressive histology, high Ki-67 proliferation rate and …

Tp53 Mutation Is Frequent In Mantle Cell Lymphoma With Ezh2 Expression And Have Dismal Outcome When Both Are Present, Do Hwan Kim, Saima Siddiqui, Preetesh Jain, Michael Wang, Beenu Thakral, Shaoying Li, Roberto Miranda, Francisco Vega, L Jeffrey Medeiros, Chi Young Ok

Faculty, Staff and Student Publications

Enhancer of zeste homolog 2 (EZH2) expression is found in about 40% of mantle cell lymphoma (MCL) patients, which is associated with aggressive histology, high Ki-67 proliferation rate, p53 mutant pattern and inferior overall survival (OS). We conducted 11-gene (ATM, BIRC3, CCND1, KMT2C, KMT2D, NOTCH1, NOTCH2, RB1, TP53, TRAF2 and UBR5) next generation sequencing panel to shed more light on MCL with EZH2 expression (EZH2+ MCL). EZH2+ MCL more frequently harbor TP53 mutation compared to EZH2(-) MCL (41.2% vs. 19.1%, respectively, p = 0.045). TP53 mutation and EZH2 expression demonstrated overlapping features including aggressive histology, high Ki-67 proliferation rate and …

Cranio-Cervical Abnormalities In Moderate-To-Severe Osteogenesis Imperfecta – Genotypic And Phenotypic Determinants, Juliana Marulanda, Jean-Marc Retrouvey, Brendan Lee, V Reid Sutton, Frank Rauch, Michelle Briner

Faculty, Staff and Students Publications

INTRODUCTION: Cranio-cervical anomalies are significant complications of osteogenesis imperfecta (OI), a rare bone fragility disorder that is usually caused by mutations in collagen type I encoding genes.

OBJECTIVE: To assess cranio-cervical anomalies and associated clinical findings in patients with moderate-to-severe OI using 3D cone beam computed tomography (CBCT) scans.

METHODS: Cross-sectional analysis of CBCT scans in 52 individuals with OI (age 10-37 years; 32 females) and 40 healthy controls (age 10-32 years; 26 females). Individuals with a diagnosis of OI type III (severe, n = 11), type IV (moderate, n = 33) and non-collagen OI (n = 8) were recruited …

Tmem106b Coding Variant Is Protective And Deletion Detrimental In A Mouse Model Of Tauopathy, George A Edwards, Caleb A Wood, Yang He, Quynh Nguyen, Peter J Kim, Ruben Gomez-Gutierrez, Kyung-Won Park, Yong Xu, Cody Zurhellen, Ismael Al-Ramahi, Joanna L Jankowsky

Duncan NRI Faculty and Staff Publications

TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and …

Variants In Zfx Are Associated With An X-Linked Neurodevelopmental Disorder With Recurrent Facial Gestalt\, James L Shepherdson, Katie Hutchison, Dilan Wellalage Don, George Mcgillivray, Tae-Ik Choi, Carolyn A Allan, David J Amor, Siddharth Banka, Donald G Basel, Laura D Buch, Deanna Alexis Carere, Renée Carroll, Jill Clayton-Smith, Ali Crawford, Morten Dunø, Laurence Faivre, Christopher P Gilfillan, Nina B Gold, Karen W Gripp, Emma Hobson, Alexander M Holtz, A Micheil Innes, Bertrand Isidor, Adam Jackson, Panagiotis Katsonis, Leila Amel Riazat Kesh, Genomics England Research Consortium;, Sébastien Küry, François Lecoquierre, Paul Lockhart, Julien Maraval, Naomichi Matsumoto, Julie Mccarrier, Josephine Mccarthy, Noriko Miyake, Lip Hen Moey, Andrea H Németh, Elsebet Østergaard, Rushina Patel, Kate Pope, Jennifer E Posey, Rhonda E Schnur, Marie Shaw, Elliot Stolerman, Julie P Taylor, Erin Wadman, Emma Wakeling, Susan M White, Lawrence C Wong, James R Lupski, Olivier Lichtarge, Mark A Corbett, Jozef Gecz, Charles M Nicolet, Peggy J Farnham, Cheol-Hee Kim, Marwan Shinawi

Duncan NRI Faculty and Staff Publications

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included …

Comprehensive Immunogenomic Profiling Of Idh1-/2-Altered Cholangiocarcinoma, Shalini Makawita, Sunyoung Lee, Elisabeth Kong, Lawrence N Kwong, Zeyad Abouelfetouh, Anaemy Danner De Armas, Lianchun Xiao, Karthikeyan Murugesan, Natalie Danziger, Dean Pavlick, Anil Korkut, Jeffrey S Ross, Milind Javle

Faculty, Staff and Student Publications

Purpose: Isocitrate dehydrogenase (IDH)1/2 genomic alterations (GA) occur in 20% of intrahepatic cholangiocarcinoma (iCCA); however, the immunogenomic landscape of IDH1-/2-mutated iCCA is largely unknown.

Methods: Comprehensive genomic profiling (CGP) was performed on 3,067 cases of advanced iCCA. Tumor mutational burden (TMB), PD-L1 expression (Dako 22C3), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH) as a surrogate marker for homologous recombination deficiency were examined. RNA sequencing of 73 patient samples was analyzed for differences in stromal/immune cell infiltration, immune marker expression, and T-cell inflammation. Tissue microarray arrays were subjected to multiplex immunohistochemistry and colocalization …

A Small Molecule With Big Impact: Mrtx1133 Targets The Krasg12d Mutation In Pancreatic Cancer, Daoyan Wei, Liang Wang, Xiangsheng Zuo, Anirban Maitra, Robert S Bresalier

Faculty, Staff and Student Publications

KRAS mutations drive oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have KRAS mutations, with G12D (∼42% of cases) and G12V (∼32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS-mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, noncovalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent …

Drug Resistance Assessed In A Phase 3 Clinical Trial Of Maribavir Therapy For Refractory Or Resistant Cytomegalovirus Infection In Transplant Recipients, Sunwen Chou, Sophie Alain, Carlos Cervera, Roy F Chemaly, Camille N Kotton, Jens Lundgren, Genovefa A Papanicolaou, Marcus R Pereira, Jingyang J Wu, Rose Ann Murray, Neil E Buss, Martha Fournier

Faculty, Staff and Student Publications

Background: This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56% and 24%, respectively, cleared cytomegalovirus DNA at week 8 (treatment responders).

Methods: Baseline and posttreatment plasma samples were tested for mutations conferring drug resistance in viral genes UL97, UL54, and UL27.

Results: At baseline, genotypic testing revealed resistance to ganciclovir, foscarnet, or cidofovir in 56% of patients receiving maribavir and 68% receiving IAT, including 9 newly phenotyped mutations. Among them, 63% (maribavir) and 21% (IAT) were treatment responders. Detected baseline maribavir resistance mutations were UL27 L193F (n …