Medical Genetics Commons^™

Genetics Of Cerebrotendinous Xanthomatosis, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Cerebrotendinous xanthomatosis (CTX) is rare, autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in CYP27A1, which encodes sterile 27 hydroxylase, a key enzyme in bile acid biosynthesis. Enzyme deficiency results in reduced cholic and chenodeoxycholic acid synthesis with accumulation of cholestanol, bile acid intermediates, and bile alcohols, producing a progressive multisystem disorder characterized by chronic diarrhea, juvenile-onset cataracts, tendons xanthomas, and neurological dysfunction. Although CTX typically begins in childhood, diagnosis is frequently delayed until adulthood, limiting the benefit of effective disease modifying therapy with chenodeoxycholic acid. Since the identification of CYP27A1, more than 200 pathogenic variants have …

Unraveling The Nexus: Tumor Mutational Burden, Pd-L1 Expression, And Oncogenic Alterations In Non-Small Cell Lung Cancer Cytology Specimens, Min Dai, Francis Anthony San Lucas, Hector Alvarez, Leomar Ballester, Hui Chen, Keyur P Patel, Asif Rashid, Shun Rao, Mark J Routbort, Gloria Sura, Keith Sweeney, Gokce Toruner, Peng Wei, Richard Yang, Hyvan Dang, Rajyalakshmi Luthra, Sinchita Roy-Chowdhuri

Faculty, Staff and Student Publications

Background: PD-L1 expression and tumor mutational burden (TMB) are biomarkers for immune checkpoint inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC); however, patients harboring oncogenic alterations have limited benefit from ICIs. The impact of oncogenic alterations on TMB and PD-L1 tumor proportion score in lung cytology specimens is poorly understood. Herein, the association between oncogenic alterations, TMB, and PD-L1 in NSCLC cytology specimens is explored.

Methods: Next-generation sequencing results from 312 NSCLC cytology specimens were retrospectively reviewed that interrogate 610 genes and select immuno-oncology signatures. TMB and PD-L1 immunohistochemical expression across oncogenic alterations were analyzed to explore associations.

Results: …

Baseline Parp-1 Pet Imaging In Patients With Advanced Solid Tumors With Dna Damage Response Mutations, Tarek Daoud, Jiansong Chen, Peng Wei, Franklin Wong, Timothy A Yap, Lilie L Lin

Faculty, Staff and Student Publications

Purpose: Inhibitors of poly(ADP-ribose) polymerase (PARP), an enzyme with numerous roles in DNA damage response signaling, represent a class of anti-cancer drugs approved for treating solid tumors with defects in the DNA damage response. However, additional methods for identifying patients who would benefit from the use of PARP inhibitors are urgently needed. We evaluated a novel radiotracer, 18F-FluorThanatrace ([18F]-FTT), to noninvasively assess PARP activity with PET/CT before treatment and determine associations between uptake, tumor mutation status, and prior receipt of therapy including PARP inhibitors.

Methods: Fifty-two patients with solid tumors underwent whole-body (skull base to thigh) [18F]-FTT PET/CT scans before …

Impact Of Mutational Landscape And Burden On Rbc Transfusion Response In Patients With Lower-Risk Myelodysplastic Syndromes (Lr-Mds) In The Commands Study, Rami S Komrokji, Sheida Hayati, Manuel Ugidos, Guillermo Garcia-Manero, Matteo Giovanni Della Porta, Amer M Zeidan, Valeria Santini, Uwe Platzbecker, Anita K Gandhi, Rajasekhar N V S Suragani

Faculty, Staff and Student Publications

The COMMANDS trial established luspatercept as a first‐line treatment for anemia in transfusion‐dependent lower‐risk (LR) myelodysplastic syndromes (MDS). Here we report red blood cell (RBC) transfusion response analysis based on somatic mutations profile and disease risk for patients treated with luspatercept or epoetin alfa in the COMMANDS trial. Of 350 evaluable patients, 238 (68.0%) had MDS with multiple lineage dysplasia and ring sideroblasts (RS) according to World Health Organization 2016 criteria, and 320 (91.4%) had somatic mutations in ≥ 1 gene (median, 2) with median variant allele frequencies (VAF) of 2%–59%. Mutation profiles were similar in the treatment groups. Luspatercept …

Quantifying Rate-Limiting Genetic Variation In Breast And Ovarian Tumourigenesis, Kathleen E Houlahan, Mahad Bihie, Yves Greatti, Julián Grandvallet Contreras, Daniel J Fulop, Gonzalo Lopez, Marc Williams, Hsin-Hsiung Huang, Peter Van Loo, Paul C Boutros, Kuan-Lin Huang

Faculty, Staff and Student Publications

Background: The number and type of genetic alterations required to initiate breast and ovarian cancer remain unclear. While germline BRCA1/2 carriers show markedly elevated cancer risk, it is uncertain whether point mutations or copy number alterations constitute the rate-limiting events of tumourigenesis.

Methods: We developed a statistical framework extending prior incidence-mutation models to estimate the minimal number and type of driver events required for cancer initiation. Somatic mutation and copy-number data from >3000 breast and ovarian cancers in TCGA and METABRIC were compared between germline BRCA1/2 carriers and non-carriers matched on subtypes. Results were validated through analyses of evolutionary timing …

Lonp1 Variants Are Associated With Clinically Diverse Phenotypes, Randee E Young, Lu Qiao, Rebecca Hernan, David A Sweetser, Jessica L Waxler, Daryl A Scott, Tiana M Scott, Seema R Lalani, Mahshid S Azamian, Jill A Rosenfeld, Bret Bostwick, Lindsay C Burrage, Lance H Rodan, Bianca E Russell, Marina Dutra-Clarke, Michael Kruer, Somayeh Bakhtiarim, Hossein Darvish, David J Amor, Shamima Rahman, Karen Stals, Lisa Bradley, Susan Byrne, Leandra K Tolusso, Beatrix Wong, Laura Benedict, Kimberly Wallis, Kestutis Micke, Cindy Colson, Thomas Smol, Sabrina V Southwick, Kristen A Miller, Michelle L Kush, Odelia Chorin, Annick Rothschild, Wei Wang, Yufeng Shen, Wendy K Chung

Faculty, Staff and Students Publications

LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic …

Risk Stratification Of Low-Dose Cytarabine And Venetoclax In Patients With Aml Ineligible For Intensive Chemotherapy, Andrew H Wei, Panayiotis Panayiotidis, Pau Montesinos, Kamel Laribi, Vladimir Ivanov, Inho Kim, Jan Novak, Rebecca Champion, Walter Fiedler, Maria Pagoni, Julie Bergeron, Stephen B Ting, Jing-Zhou Hou, Takahiro Yamauchi, Jianxiang Wang, Stephen A Strickland, Michael R Savona, Tara L Lin, Anoop Enjeti, Ing Soo Tiong, Sangmin Lee, Gail J Roboz, Relja Popovic, Qi Jiang, Zihuan Liu, Yan Sun, Wellington Mendes, Brenda Chyla, Courtney D Dinardo

Faculty, Staff and Student Publications

Prognostic risk categorization aids treatment selection for patients with acute myeloid leukemia (AML). Although the European LeukemiaNet (ELN) classifications (2017 and 2022) for AML have been used to stratify outcomes for patients receiving intensive chemotherapy, their application to patients receiving less intensive therapy, such as azacitidine plus venetoclax, has been less satisfactory. In response, a 4-gene classifier that stratifies older patients with AML unfit for intensive chemotherapy into those with higher benefit (wild type), intermediate benefit (FLT3-internal tandem duplication [ITD] or NRAS/KRAS mutation), or lower benefit (TP53 mutation) after azacitidine plus venetoclax treatment was developed. We hypothesized that this 4-gene …

Supt16h-Associated Neurodevelopmental Disorder And Neurocristopathy: Genetic And Phenotypic Spectrum, Eunhye Lee, Seungmin Sim, Hee-Jung Choi, Eugene Y Liang, Carolyn Le, Roya Bina, Ryan Cohen, Elizabeth George, Soo Yeon Kim, Gifty Bhat, Erin Falsey, Richard Sidlow, Kristin Clinard, Shay Ben-Shachar, Eleina England, Beatriz Menendez, Isabella Herman, Shelly Nielsen, Jaya Punetha, Priya Bhola, J Austin Hamm, Megan A Keeney, Nike Sitzman, Sara Berger, Lakshmi Mehta, Alison J Conn, Lilian Downie, Myla Ashfaq, Hope Northrup, Ange-Line Bruel, Sylvie Odent, Justin O Szot, Noelia Nunez Martinez, Sunju Park, Julie Refkin, Jean-Marc Good, Fabienne Maurer, Cédric Le Caignec, David J Coman, Erin Anderson, Linda J Richards, Ryan J Dean, Caleb Yang, Chulwon Choi, Byung Joon Hwang, Jin Sook Lee, William B Dobyns, Murim Choi, Elliott H Sherr, Jong-Hee Chae, Yun Kee, Emanuela Argilli

Faculty, Staff and Student Publications

SUPT16H encodes a subunit of the FACT (FAcilitates Chromatin Transcription) complex, a histone chaperone essential for maintaining chromatin integrity during transcription, replication, and DNA repair. Pathogenic de novo SUPT16H missense variants have previously been linked to neurodevelopmental disorders in eight individuals. Here, we expand the genotypic and phenotypic spectrum by identifying 24 additional individuals harboring ultrarare heterozygous missense or truncating variants, who share overlapping clinical features including intellectual disability, autism spectrum disorder, hypotonia, and characteristic craniofacial dysmorphism. To elucidate the underlying mechanisms, we generated a supt16h knockout zebrafish model using CRISPR/Cas9. The supt16h loss-of-function (LOF) model recapitulated key patient phenotypes …

Bi-Allelic Variants In Neuronal Adhesion Molecule Astrotactin 1 Gene Astn1 Cause Diverse Neurodevelopmental Disorders, Jesse M Levine, Daniel G Calame, Riccardo Sangermano, Haowei Du, Ahmed Saad, Jasmin Lisfeld, Tatjana Bierhals, Jonas Denecke, Eyyup Uctepe, Merve Yoldas Celik, Ahmet Yesilyurt, Hilal Yildiz Er, Elif Yilmaz Gulec, Aziza Mushiba, Naif Almontashiri, Pawel Gawlinski, Wojciech Wiszniewski, Ender Karaca, Lama Alabdi, Davut Pehlivan, Dana Marafi, Maha S Zaki, Fowzan S Alkuraya, Joseph G Gleeson, Shalini N Jhangiani, Richard A Gibbs, Jennifer E Posey, Kinga M Bujakowska, James R Lupski

Faculty, Staff and Students Publications

ASTN1 encodes astrotactin 1, a neuronal-glial ligand in the developing brain that promotes neuronal migration along radial glia in brain structures with laminar organization, such as the cerebral cortex, hippocampus, and cerebellum. In mouse models, disruption of Astn1 results in neuronal migration deficits, a mild reduction in cerebellar volume, and balance and coordination deficits. In humans, bi-allelic ASTN1 variants have been identified in nine individuals with neurodevelopmental disorders (NDDs) with or without brain malformations. ASTN1 additionally interacts with astrotactin 2 (ASTN2) to implement neuronal migration; ASTN2 deletions associate with NDDs with reduced penetrance. Here, we describe eighteen individuals with NDDs …

Ubiquitination Of Oncogenic Mutant P53 Via Attenuation Of Ribosome Biogenesis Machinery Effectively Inhibits Pancreatic Tumor Growth, Mudassier Ahmad, Sahir Sultan Alvi, Haider Ahsan, Carlos Perez, Andrew Massey, Vivek K Kashyap, Neeraj Chauhan, Emmanuel Anning, Manish K Tripathi, Dae J Kim, Nirakar Sahoo, Tamer Oraby, Murali M Yallapu, Mohammad Moshahid Khan, Manu M Sebastian, Subhash C Chauhan, Bilal B Hafeez

Faculty, Staff and Student Publications

Dysregulated ribosome biogenesis and p53 mutations are known to play oncogenic roles in various cancers, including pancreatic cancer. In this study, we demonstrated the therapeutic potential of BMH-21, a pharmacologic inhibitor of RNA polymerase I, against pancreatic cancer by uncovering a novel molecular mechanism involving RPA194-mediated ubiquitination of mutant p53 without affecting the ubiquitination of wild-type p53. Our key findings are that (i) BMH-21 selectively induces apoptosis and cell growth inhibition of pancreatic cancer cells with no effect on normal human pancreatic ductal epithelial cells; (ii) BMH-21 degrades RPA194; (iii) BMH-21 inhibits recruitment of both RPA194 and RPA135 on rDNA …

Rare Heterozygous Missense Variants In Vsx2 Are Associated With Retinal Detachment, Daniel C Brock, Justin S Dhindsa, Yifan Chen, Vida Ravanmehr, Jonathan Mitchell, Fengyuan Hu, Xiaoyin Li, Likhita Nandigam, Quanli Wang, Kevin Wu, Jessica C Butts, Hardeep S Dhindsa, Benjamin J Frankfort, Nicholas M Tran, Slavé Petrovski, Ryan S Dhindsa

Duncan NRI Faculty and Staff Publications

Retinal detachment (RD) is a sight-threatening emergency requiring urgent intervention to prevent permanent vision loss. While both environmental and genetic risk factors contribute to RD, its complete genetic architecture remains unknown. Here, we performed the largest whole genome sequencing-based case-control study in RD to date, including data from 7,276 RD cases and 236,741 controls in the UK Biobank. Through variant- and gene-level association analyses, we identified VSX2 as a genetic determinant of RD risk while confirming established associations including FAT3, RDH5, and COL2A1. Gene-level collapsing analysis revealed that rare heterozygous missense variants in VSX2 confer a 2.8-fold …

Acta2 Pathogenic Variants Activating Heat Shock Factor 1 And Increasing Cholesterol Biosynthesis In Smooth Muscle Cells Predispose To Early Onset Atherosclerosis, Maura L Boerio, Abhijnan Chattopadhyay, Xue-Yan Duan, Aamuktha Karla, Ernesto Calderon Martinez, Amelie Pinard, Andrew K Morse, Darshan Reddy, Sree Dharma, Walter Velasco-Torrez, Julien Marcadier, Siddharth K Prakash, Sherene Shalhub, Julie De Backer, Richmond Jeremy, Shaine A Morris, Anji T Yetman, Alan C Braverman, Dianna M Milewicz

Faculty, Staff and Student Publications

Background: ACTA2 pathogenic variants predispose to thoracic aortic disease, and a subset of variants lead to early onset atherosclerotic cardiovascular disease (ASCVD). The molecular pathway linking misfolded SMA (α-smooth muscle actin) monomers to augmented atherosclerosis-associated smooth muscle cell phenotypic modulation can be modeled in vitro by stably expressing the ACTA2 p.R149C variant in Acta2-/- smooth muscle cells.

Methods: The Montalcino Aortic Consortium patient registry was used to identify cases with ACTA2 pathogenic/likely pathogenic missense variants. These patients were surveyed, and medical records were reviewed, to identify cases with early onset ASCVD. The variants for these cases, as well as …

Presenilin L166p Mutation, A Model Of Familial Alzheimer's Disease, Leads To Early Onset Bone Loss, Vidyani Suryadevara, Connor J Krehbial, Anuradha K Valiya, Melinda Vang, Julian Balanta-Melo, Pierre P Eleniste, Sumana Posritong, Jung Min Hong, Katie Chester, Gabriel M Pagnotti, Teresita Bellido, Monte S Willis, Angela Bruzzaniti

Faculty, Staff and Student Publications

Accelerated bone loss has been reported in the early stages of Alzheimer's disease (AD) as indicated by reduced bone mineral density and increased fracture risk in these patients, compared to healthy individuals. In the present study, we investigated bone loss in mouse models of familial Alzheimer's disease harboring the Presenilin 1 (L166P) knock-in mutation (PSEN1 KI), with or without the human amyloid precursor protein transgene (hAPP Tg+) known to induce brain amyloid pathology by 6 months. Female and not male 12-month PSEN1/hAPP Tg+ mice exhibited reduced whole-body bone mineral density and bone mineral content, compared to sex-matched controls. Consistent with …

The Origin Of Hepatocellular Carcinoma Depends On Metabolic Zonation, Jason Guo, Roger Liang, Andrew Chung, Zhijie Li, Boyuan Li, Eric Chen, Lin Li, Jingjing Wang, Meng-Hsiung Hsieh, Ivy Xiangyi Fang, Benjamin Kroger, Yunguan Wang, Min Zhu, Xiongzhao Ren, Greg Mannino, Yuemeng Jia, Yonglong Wei, Stephen Moore, Daniel J Siegwart, Stephen S Chung, Zixi Wang, Tripti Sharma, Suman Komjeti, Yi Han, Purva Gopal, Guanghua Xiao, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

The origin of cancer is poorly understood because premalignant cells are rarely followed in their native environments. Although the spatial compartmentalization of metabolic functions is critical for proper liver function, it is unknown whether cancers arise from some zones but not others and whether there are metabolic determinants of cancer risk. Zone-specific, mosaic introduction of Ctnnb1 (catenin beta 1) and Arid2 (AT-rich interaction domain 2) mutations, commonly co-mutated genes in hepatocellular carcinoma (HCC), in mouse models showed that position and metabolic context determine clone fates. Ctnnb1/Arid2-driven cancers were much more likely to arise in zone 3. The …

Using The Linear References From The Pangenome To Discover Missing Autism Variants, Yang Sui, Jiadong Lin, Michelle D Noyes, Youngjun Kwon, Isaac Wong, Nidhi Koundinya, William T Harvey, Mei Wu, Kendra Hoekzema, Katherine M Munson, Gage H Garcia, Jordan Knuth, Julie Wertz, Tianyun Wang, Kelsey Hennick, Druha Karunakaran, Rafael A Polo Prieto, Rebecca Meyer-Schuman, Fisher Cherry, Davut Pehlivan, Bernhard Suter, Jonas A Gustafson, Danny E Miller, Human Pangenome Reference Consortium (Hprc), Hanna Berk-Rauch, Tomasz J Nowakowski, Aravinda Chakravarti, Huda Y Zoghbi, Evan E Eichler

Duncan NRI Faculty and Staff Publications

To better understand large-effect pathogenic variation associated with autism, we generated long-read sequencing (LRS) data to construct phased and near-complete genome assemblies (average contig N50 = 43 Mbp, QV = 56) for 189 individuals from 51 families with unsolved cases. We applied read- and assembly-based strategies to facilitate comprehensive characterization of de novo mutations, structural variants (SVs), and DNA methylation. Using LRS pangenome controls, we efficiently filtered >97% of common SVs exclusive to 87 offspring. We find no evidence of increased autosomal SV burden for probands when compared to unaffected siblings yet observe a suggestive trend toward an increased SV …

De Novo Variants In The Splicing Factor Gene Sf3b1 Are Associated With Neurodevelopmental Disorders, Kevin Uguen, Tiffany Bergot, Marie-Pier Scott-Boyer, Solène Chapalain, Camille Desdouets, Séverine Commet, Changlian Zhu, Yiran Xu, Yangong Wang, Tony Roscioli, Frederic Tran-Mau-Them, Laurence Faivre, Julien Maraval, Julian Delanne, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Céline Jost, Marc Planes, Susan Hiatt, Patricia Wheeler, Claudia Gonzaga-Jauregui, Heng Wang, Baozhong Xin, Valerie Sency, Michael C Kruer, Somayeh Bakhtiari, Patrick Sulem, Cynthia Curry, Trine Prescott, Gertrud Strobl-Wildemann, Theresa Brunet, Martine Doco Fenzy, Thomas Courtin, Céline Poirsier, Trine Bjørg Hammer, Christina D Fenger, Melissa Macpherson, Kosuke Izumi, Jacqueline Leonard, Dong Li, Elaine H Zackai, Ian A Glass, Scott Ward, Philippe M Campeau, Maria Carla Hermida Borroto, Laurence Le Moigno, Hilde Van Esch, Liesbeth De Waele, Daniel G Calame, James R Lupski, Giulia Barcia, Cristina Peduto, Pauline Planté-Bordeneuve, Lucie Dupuis, Roberto Mendoza-Londono, Dimitri J Stavropoulos, Jennifer Gillibert-Duplantier, Thomas Besnard, Laura Do Souto Ferreira, Benjamin Cogné, Stéphane Bézieau, Arnaud Droit, Laurent Corcos, Eric Lippert, Claude Férec, Sebastien Küry, Delphine G Bernard

Faculty, Staff and Students Publications

SF3B1 is an essential and ubiquitous splicing factor that plays a pivotal role in the early steps of pre-mRNA splicing. Recurrent somatic missense mutations in SF3B1 are frequent in cancers, but no constitutional variant has been reported so far. We describe here a cohort of 26 individuals with neurodevelopmental disorders, harbouring SF3B1 constitutional heterozygous variants that appeared mostly de novo. Patients present with a global developmental delay, associated with variable neurological and facial dysmorphic traits. A dichotomy may emerge between patients harbouring predicted loss of function (n = 9) and missense variants (n = 17), the latter being associated with …

Tet2-Mutant Clonal Hematopoiesis Enhances Macrophage Antigen Presentation And Improves Immune Checkpoint Therapy In Solid Tumors, Shelley Herbrich, Mehdi Chaib, Swetha Anandhan, Samuel W Andrewes, Ashwat Nagarajan, Baoxiang Guan, Nishant Gandhi, Jared Gilliam, Milan Radovich, Padmanee Sharma

Faculty, Staff and Student Publications

Clonal hematopoiesis (CH) is detectable in upwards of 20% of patients with solid tumors and is associated with worsened prognosis; however, its role in tumor immunology and immune checkpoint therapy (ICT) is unknown. Using a bone marrow chimera model of Tet2+/mut CH in mice with solid tumors, we found the Tet2-mutant myeloid cells are abundant in the tumor microenvironment and contributed to an improved response to ICT. Mechanistically, Tet2+/mut macrophages inside the tumor act as immunogenic antigen-presenting cells that more effectively cross-prime naive CD8+ T cells in response to IFNγ. In human cohorts of 35,971 non-small cell lung cancer patients …

Inhibition Of Gpx4 Induces The Death Of P53-Mutant Triple-Negative Breast Cancer Cells, William M Tahaney, Amanda Lanier, Jing Qian, Cassandra L Moyer, Nghi Nguyen, Yanxia Ma, Jamal Hill, Reid T Powell, Clifford C Stephan, Peter J A Davies, Abhijit Mazumdar, Powel H Brown

Faculty, Staff and Student Publications

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high rates of tumor protein 53 (TP53) mutation and with limited targeted therapies. Despite being clinically advantageous, direct targeting of mutant TP53 has been challenging. Therefore, we hypothesized that p53-mutant TNBC cells rely upon other potentially targetable survival pathways.

Methods: In vitro and in silico screens were used to identify drugs that induced preferential death in TP53-mutant cells. The effect of the ferroptosis inducer ML-162 was tested both in vitro and in vivo and the mechanism of cell death following ML-162 treatment or GPX4 knockout was …

35 Individuals With Huwe1-Related Neurodevelopmental Disorder And Suggested Clinical Evaluations, Mindy H. Li, Deziree L. Coleman, Kelsey Hogan, Danielle Luz, Lindsay Bhandari, Newell Belnap, Tiffany Busa, Charles Coutton, Klaus Dieterich, Svetlana Gorokhova, Clara Hildebrandt, Rachel Logan, Milena Mariani, Manuela Morleo, Vincenzo Nigro, John Pappas, Rachel Rabin, Kelly Schoch, Angelo Selicorni, Vandana Shashi, Rebecca Spillman, Jennifer Sullivan, Charlotte Tardy, Samantha A. Schrier Vergano, Brock Grill, Kristin Baranano

Department of Pediatrics Faculty Publications

HUWE1 (HECT, UBA, and WWE Domain Containing E3 Ubiquitin Protein Ligase1, OMIM 300697), located at Xp11.22, encodes a ubiquitin ligase that is highly conserved across species. Genetic variants in HUWE1 described in multiple independent studies cause X-linked intellectual disability, including in the patients identified by Juberg, Marsidi, and Brooks. This report describes 35 additional cases of individuals with variants in HUWE1 and suggested guidelines for clinical management. Our study includes several female cases, which have not been widely reported previously. Our findings confirm earlier reported clinical features including developmental delay, autism, hypotonia, short stature, and dysmorphic facial features as well …

The Lysine Demethylase Kdm4c Is An Oncogenic Driver And Regulates Erk Activity In Kras-Mutant Pancreatic Ductal Adenocarcinoma, Menna-T-Allah Shaheen, Sarah Dhebat, Kimal I Rajapakshe, Bidyut Ghosh, Benson Chellakkan Selvanesan, Shariq S Ansari, Cara L Haymaker, Dorsay Sadeghian, Huamin Wang, Ching-Fei Li, Haoqiang Ying, Anirban Maitra

Faculty, Staff and Student Publications

Deregulation of proteins involved in chromatin regulation is common in pancreatic ductal adenocarcinoma (PDAC). Lysine demethylase 4C (KDM4C) is one of the chromatin-modifying proteins frequently overexpressed across multiple solid cancers and is linked to chromatin instability, increased cell proliferation, and enhanced stem cell–like behavior. We observed upregulation of KDM4C protein in a panel of human PDAC cell lines and patient samples compared with nonneoplastic controls. CRISPR/Cas9-mediated deletion of KDM4C in human and murine PDAC cells reduced proliferation, clonogenicity, and increased survival of orthotopically implanted murine PDAC allografts. Transcriptomic and proteomic analyses revealed that loss of KDM4C in both human and …

Clinical And Molecular Characteristics Of Patients With Young-Onset And Average-Onset Pancreatic Adenocarcinoma, Adriana C Gamboa, Kever A Lewis, Laura R Prakash, Zhouxuan Li, Wei Qiao, Dan Zhao, Mark W Hurd, Mahmoud Yousef, Naruhiko Ikoma, Michael P Kim, Jeffrey E Lee, Jessica E Maxwell, Ching-Wei D Tzeng, Matthew H G Katz, Rebecca A Snyder

Faculty, Staff and Student Publications

Purpose: The incidence of young-onset pancreatic cancer (YO-PC) has risen over the past two decades, yet its molecular characteristics and long-term outcomes remain poorly defined.

Methods: We retrospectively evaluated patients with PC treated at a tertiary referral center from 2016 to 2022 who had available molecular data. Patients were classified as YO-PC (≤50 years) or average-onset PC (AO-PC, >50 years). A subset analysis examined outcomes in those who underwent curative-intent pancreatectomy. Primary end points included overall survival (OS) and recurrence-free survival (RFS).

Results: Among 511 patients, 10.9% had YO-PC (n = 56; median age 44 years). Patients with YO-PC more …

Prickle4 Drives Microenvironmental Remodeling And Resistance To Parp Inhibition In Idh-Mutant Glioma, Ju Yang, Hua Yang, Yifan Yuan, Chenyang Zhang, Ziwei Fu, Yanyan Chen, Yinghong Xiong, Shuyu Chen, Kexin Ling, Ying Liu, Jason T Huse, Bo Chen, Timothy A Chan, Zengxin Qi, Zhao Zhang, Xiuping Liu, Yuxiang Wang

Faculty, Staff and Student Publications

Mutations in isocitrate dehydrogenase (IDH) genes sensitize gliomas to PARP inhibition (PARPi) by inducing epigenetic reprogramming of DNA damage repair circuits. However, tumors treated with PARPi eventually relapse despite initial responsiveness. In this study, it is demonstrated that the anti-angiogenic agent lenvatinib synergizes effectively with PARPi, resulting in substantial tumor regression and significantly extended survival. Genomic analysis of tumors reveals that PARPi induces widespread transcriptomic changes that are predominantly pro-inflammatory, thereby promoting tumor angiogenesis. Prickle4, a planar cell polarity protein, is identified as a critical mediator of PARPi-induced neovascularization. Targeting Prickle4 effectively overcomes PARPi resistance in these tumors. Collectively, these …

Endogenous Processes Underlying Clock-Like Mutational Signatures, Teresa Druck, Rami I Aqeilan, C Marcelo Aldaz, Nicola Zanesi, Kay Huebner

Faculty, Staff and Student Publications

Wellcome Trust scientists have shown that “mutational signatures” in specific nucleotide contexts accumulate in genomes of mammalian tissues, providing clues to underlying causes of specific signatures. Analysis of cancer genomes has identified more than 50 single‐base substitution (SBS) signatures, with SBS1, SBS5, and SBS40 linked to aging and present in normal tissues. SBS1 results from cytosine demethylation, whereas SBS5 and SBS40 arise from unknown endogenous mechanisms. We hypothesized that loss of fragile‐site genes drives these two signatures. FHIT, located at FRA3B, is frequently deleted in cancers, and Fhit‐deficient mouse tissues exhibit a mutation profile resembling human SBS5. Data mining of …

Genomic Determinants Of Response And Resistance To Pirtobrutinib In Relapsed/Refractory Chronic Lymphocytic Leukemia, Jennifer R Brown, Bastien Nguyen, Sai Prasad Desikan, Helen Won, Shady I Tantawy, Samuel C Mcneely, Narasimha Marella, Hetal S Randeria, Lauren M Hanson, Andrew Parker, Salomé Calado Botelho, Jennifer A Woyach, Krish Patel, Constantine S Tam, Toby A Eyre, Chan Y Cheah, Nirav N Shah, Paolo Ghia, Wojciech Jurczak, Minna Balbas, Binoj Nair, Paolo Abada, Chunxiao Wang, Denise Wang, Lindsey E Roeker, Varsha Gandhi, William G Wierda

Faculty, Staff and Student Publications

Pirtobrutinib, a noncovalent, reversible Bruton tyrosine kinase inhibitor (BTKi), demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), resistant to covalent BTKi (cBTKi). We analyzed genomic correlations with response and resistance to pirtobrutinib in relapsed/refractory (R/R) patients with CLL pretreated with cBTKi enrolled in the phase 1/2 BRUIN trial. DNA sequencing was performed on peripheral blood mononuclear cells at baseline, on treatment, and at progressive disease (PD). Common alterations at baseline included mutations in BTK (43%), TP53 (38%), SF3B1 (25%), NOTCH1 (23%), ATM (19%), XPO1 (11%), PLCG2 (9%), BCL2 (8%), and 17p deletion (28%). Common baseline BTK mutations included C481S …

Engineering Mutation Clones In Mammalian Cells With Crispr/Cas9, Zijun Huo, Jian Tu, Rachel Shoemaker, Dung-Fang Lee, Ruiying Zhao

Faculty, Staff and Student Publications

CRISPR, Clustered Regularly Interspaced Short Palindromic Repeat, as a powerful genome engineering system, has been widely accepted and employed in gene editing of a vast range of cell types. Compared to zinc finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs), CRISPR shows a less complicated process and higher efficiency. With the development of different CRISPR systems, it can be used not only to knock out a gene but also to make precise modifications, activate or repress target genes with epigenetic modifications, and even for genome wide screening. Here we will describe the procedure of generating a stable cell line …

Case Series Of Nizon-Isidor Syndrome By Heterozygous Variants In Med12l With Further Evidence Of Mitotic Instability In One Case With Diploid-Triploid Mosaicism, Russell Stewart, Kimberly M Ezell, Deanna S Bell, Brian Corner, Ashley Mcminn, Joy D Cogan, Rizwan Hamid, Lynette Rives, John A Phillips, Nina Paddu, Gitanjali Srivastava, Ronit Marom, Farah A Ladha, Claudia Soler-Alfonso, Rachel Franciskovich, Mary Koziura, Sumit Pruthi, Gabriele Richard, Christina B Sheedy, Undiagnosed Diseases Network, Thomas Cassini

Faculty, Staff and Students Publications

Nizon-Isidor syndrome is a rare disorder caused by heterozygous variants in MED12L, with only eight documented cases in the literature. Here, we present three additional cases of this syndrome. Proband 1 was a 7-year-old female who presented with developmental delay, right-leg hemihypertrophy, laryngeal cleft, esotropia, abnormal skin pigmentation, sectoral iris hypopigmentation, dysphagia, periventricular nodular heterotopia, seizures, morbid obesity, and a pelvic kidney. Genome sequencing (GS) revealed a MED12L variant, NM_053002.5:c.3559+2T>G. Both computational models and transcriptomic analysis confirmed that this variant induced splice loss of MED12L exon 25. Probands 2 and 3 presented with overlapping phenotypes of developmental delay; sequencing …

Circulating Tumor Dna Refines Risk Stratification Of Neoadjuvant Therapy-Resistant Breast Tumors, Mark Jesus M Magbanua, Nayelis A Manon, Denise M Wolf, Samuel Rivero-Hinojosa, Ziad Ahmed, Rosalyn W Sayaman, Antony Tin, Derrick Renner, Ekaterina Kalashnikova, Lamorna Brown-Swigart, Gillian L Hirst, Christina Yau, Wen Li, Claudine Isaacs, Rebecca A Shatsky, Amy S Clark, Alexandra Zimmer, Amy L Delson, Angel Rodriguez, Minetta C Liu, Paula R Pohlmann, Laura J Esserman, Hope S Rugo, Angela Demichele, Laura Van 'T Veer

Faculty, Staff and Student Publications

Early-stage breast cancers resistant to neoadjuvant therapy (NAT), characterized by high residual cancer burden (RCB) after treatment, have an increased risk of metastatic recurrence. Here, we show that circulating tumor DNA (ctDNA) detected using a tumor-informed test (1) can improve risk stratification of patients with NAT-resistant tumors (RCB-II/RCB-III) and (2) predict response to NAT. Stratification using ctDNA status at pretreatment or post-NAT and ctDNA dynamics identified NAT-resistant tumors with a significantly decreased risk of metastatic recurrence. ctDNA clearance as early as week 3 across receptor subtypes predicted favorable responses to NAT, including immunotherapies. Interestingly, less than a fifth of patients …

Hsp90 Buffers Deleterious Genetic Variations In Brca1, Brant Gracia, Xing-Han Zhang, Patricia Montes, Tin Chanh Pham, Min Huang, Junjie Chen, Georgios Ioannis Karras

Faculty, Staff and Student Publications

Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered BRCA1 mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, by stabilizing metastable variants across the entirety …

Kras Inhibition Activates An Actionable Cd24 "Do Not Eat Me" Signal In Pancreatic Cancer, Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Zhenzhen Xun, Phuoc T Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Ching-Fei Li, Madelaine S Theardy, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Elizabeth M Park, David H Peng, Yong Zhou, Hong Zhao, Timothy P Heffernan, Andrea Viale, Huamin Wang, Stephanie S Watowich, Han Liang, Dan Zhao, Ronald A Depinho, Wantong Yao, Haoqiang Ying

Faculty, Staff and Student Publications

KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C-driven PDAC model. Compared to the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a ‘hot’ tumor immune microenvironment. Immunoprofiling revealed that CD24, a ‘don’t eat me’ signal, is significantly upregulated on cancer …

Normalization Of Temperature Effects For Quality Assurance Of Quantitative Prostate Apparent Diffusion Coefficient Imaging Across Multiple Sites, Ken-Pin Hwang, Joshua Yung, R Jason Stafford, Caroline Chung, Aradhana M Venkatesan

Faculty, Staff and Student Publications

Background: Apparent Diffusion Coefficient (ADC) as measured by diffusion weighted imaging is known to negatively correlate with prostate tumor aggressiveness. Heterogeneity in system and protocol performance causes potential variability in ADC acquired across a large scanner network, prompting a need to evaluate quantitative ADC from a prostate-specific MR diffusion protocol as part of quality assurance (QA). Due to the temperature dependence of ADC, repeatability and reproducibility assessments typically require phantoms to maintain a temperature of 0°C, imposing a considerable burden when assessing large numbers of scanners.

Purpose: To develop a QA procedure at room temperature for assessing the reproducibility of …