Genetic Phenomena Commons^™

Parp-1 Selectively Impairs Kras-Driven Phenotypic And Molecular Features In Intrahepatic Cholangiocarcinoma, Friederike L Keggenhoff, Darko Castven, Diana Becker, Stojan Stojkovic, Jovana Castven, Carolin Zimpel, Beate K Straub, Tiemo Gerber, Harald Langer, Patricia Hähnel, Thomas Kindler, Jörg Fahrer, Colm J O'Rourke, Ursula Ehmer, Anna Saborowski, Lichun Ma, Xin Wei Wang, Timo Gaiser, Matthias S Matter, Christian Sina, Stefanie Derer, Ju-Seog Lee, Stephanie Roessler, Bernd Kaina, Jesper B Andersen, Peter R Galle, Jens U Marquardt

Faculty, Staff and Student Publications

Objective: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with limited therapeutic options. KRAS mutations are among the most abundant genetic alterations in iCCA associated with poor clinical outcome and treatment response. Recent findings indicate that Poly(ADP-ribose)polymerase1 (PARP-1) is implicated in KRAS-driven cancers, but its exact role in cholangiocarcinogenesis remains undefined.

Design: PARP-1 inhibition was performed in patient-derived and established iCCA cells using RNAi, CRISPR/Cas9 and pharmacological inhibition in KRAS-mutant, non-mutant cells. In addition, Parp-1 knockout mice were combined with iCCA induction by hydrodynamic tail vein injection to evaluate an impact on phenotypic and molecular …

The Kras Mutational Spectrum And Its Clinical Implications In Pancreatic Cancer, Luigi Perelli, Giannicola Genovese, Giulio F Draetta

Faculty, Staff and Student Publications

In this issue of Cancer Cell, McIntyre et al. show that specific mutations in the KRAS proto-oncogene shape clinical progression of pancreatic ductal adenocarcinoma (PDAC). Importantly, they find that the KRASG12R mutation is enriched in early-stage PDAC, and it is characterized by distinctly activated molecular programs.

The Kras Mutational Spectrum And Its Clinical Implications In Pancreatic Cancer, Luigi Perelli, Giannicola Genovese, Giulio F Draetta

Faculty, Staff and Student Publications

In this issue of Cancer Cell, McIntyre et al. show that specific mutations in the KRAS proto-oncogene shape clinical progression of pancreatic ductal adenocarcinoma (PDAC). Importantly, they find that the KRASG12R mutation is enriched in early-stage PDAC, and it is characterized by distinctly activated molecular programs.

Single-Cell Chromatin Accessibility Reveals Malignant Regulatory Programs In Primary Human Cancers, Laksshman Sundaram, Arvind Kumar, Matthew Zatzman, Adriana Salcedo, Neal Ravindra, Shadi Shams, Bryan H Louie, S Tansu Bagdatli, Matthew A Myers, Shahab Sarmashghi, Hyo Young Choi, Won-Young Choi, Kathryn E Yost, Yanding Zhao, Jeffrey M Granja, Toshinori Hinoue, D Neil Hayes, Andrew Cherniack, Ina Felau, Hani Choudhry, Jean C Zenklusen, Kyle Kai-How Farh, Andrew Mcpherson, Christina Curtis, Peter W Laird, Cancer Genome Atlas Analysis Network, John A Demchok, Liming Yang, Roy Tarnuzzer, Samantha J Caesar-Johnson, Zhining Wang, Ashley S Doane, Ekta Khurana, Mauro A A Castro, Alexander J Lazar, Bradley M Broom, John N Weinstein, Rehan Akbani, Shwetha V Kumar, Benjamin J Raphael, Christopher K Wong, Joshua M Stuart, Rojin Safavi, Christopher C Benz, Benjamin K Johnson, Cindy Kyi, Hui Shen, M Ryan Corces, Howard Y Chang, William J Greenleaf

Faculty, Staff and Student Publications

To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting …

Dominant Missense Variants In Srebf2 Are Associated With Complex Dermatological, Neurological, And Skeletal Abnormalities, Matthew J Moulton, Kristhen Atala, Yiming Zheng, Debdeep Dutta, Dorothy K Grange, Wen-Wen Lin, Daniel J Wegner, Jennifer A Wambach, Angela L Duker, Michael B Bober, Lisa Kratz, Carol A Wise, Ila Oxendine, Anas Khanshour, Undiagnosed Diseases Network, Michael F Wangler, Shinya Yamamoto, F Sessions Cole, Jonathan Rios, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Purpose: We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation.

Methods: We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet (LD) formation to investigate the consequences …

Co-Targeting Sos1 Enhances The Antitumor Effects Of Krasg12c Inhibitors By Addressing Intrinsic And Acquired Resistance, Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann

Faculty, Staff and Student Publications

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by …

Co-Targeting Sos1 Enhances The Antitumor Effects Of Krasg12c Inhibitors By Addressing Intrinsic And Acquired Resistance, Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann

Faculty, Staff and Student Publications

Combination approaches are needed to strengthen and extend the clinical response to KRAS

The Icf Syndrome Protein Cdca7 Harbors A Unique Dna Binding Domain That Recognizes A Cpg Dyad In The Context Of A Non-B Dna, Swanand Hardikar, Ren Ren, Zhengzhou Ying, Jujun Zhou, John R Horton, Matthew D Bramble, Bin Liu, Yue Lu, Bigang Liu, Luis Della Coletta, Jianjun Shen, Jiameng Dan, Xing Zhang, Xiaodong Cheng, Taiping Chen

Faculty, Staff and Student Publications

CDCA7, encoding a protein with a carboxyl-terminal cysteine-rich domain (CRD), is mutated in immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a disease related to hypomethylation of juxtacentromeric satellite DNA. How CDCA7 directs DNA methylation to juxtacentromeric regions is unknown. Here, we show that the CDCA7 CRD adopts a unique zinc-binding structure that recognizes a CpG dyad in a non-B DNA formed by two sequence motifs. CDCA7, but not ICF mutants, preferentially binds the non-B DNA with strand-specific CpG hemi-methylation. The unmethylated sequence motif is highly enriched at centromeres of human chromosomes, whereas the methylated motif is distributed throughout …

Regulatory Complexity Of Cellular Differentiation In Candida Albicans Revealed Through Systematic Screening Of Protein Kinase Mutants, Michael C Lorenz

Faculty, Staff and Student Publications

A recent study in mBio reports the construction and preliminary screening of a library containing mutants of 99 of the 119 predicted protein kinases in Candida albicans (the majority of the remaining 20 are probably essential) (J. Kramara, M.-J. Kim, T. L. Ollinger, L. C. Ristow, et al., mBio e01249-24, 2024, https://doi.org/10.1128/mbio.01249-24). Using a quantitative competition assay in 10 conditions that represent nutritional, osmotic, cell wall, and pH stresses that are considered to model various aspects of the host environment allowed them to phenotypically cluster kinases, which highlight both the integration and specialization of signaling pathways, suggesting novel functions …

Association Of Genetic Ancestry With Molecular Tumor Profiles In Colorectal Cancer, Brooke Rhead, David M Hein, Yannick Pouliot, Justin Guinney, Francisco M De La Vega, Nina N Sanford

Faculty, Staff and Student Publications

Background: There are known disparities in incidence and outcomes of colorectal cancer (CRC) by race and ethnicity. Some of these disparities may be mediated by molecular changes in tumors that occur at different rates across populations. Genetic ancestry is a measure complementary to race and ethnicity that can overcome missing data issues and better capture genetic similarity in admixed populations. We aimed to identify somatic mutations and tumor gene expression differences associated with both genetic ancestry and imputed race and ethnicity.

Methods: Sequencing was performed with the Tempus xT NGS 648-gene panel and whole exome capture RNA-Seq for 8454 primarily …

Final Phase 1 Substudy Results Of Ivosidenib For Patients With Mutant Idh1 Relapsed/Refractory Myelodysplastic Syndrome, Courtney D Dinardo, Gail J Roboz, Justin M Watts, Yazan F Madanat, Gabrielle T Prince, Praneeth Baratam, Stéphane De Botton, Anthony Stein, James M Foran, Martha L Arellano, David A Sallman, Mohammad Hossain, Dylan M Marchione, Xiaofei Bai, Prapti A Patel, Stephanie M Kapsalis, Guillermo Garcia-Manero, Amir T Fathi

Faculty, Staff and Student Publications

Ivosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor with efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia. We report final data from a phase 1 single-arm substudy of once-daily ivosidenib in patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in …

Pkd1 Mutant Clones Within Cirrhotic Livers Inhibit Steatohepatitis Without Promoting Cancer, Min Zhu, Yunguan Wang, Tianshi Lu, Jason Guo, Lin Li, Meng-Hsiung Hsieh, Purva Gopal, Yi Han, Naoto Fujiwara, Darren P Wallace, Alan S L Yu, Xiangyi Fang, Crystal Ransom, Sara Verschleisser, David Hsiehchen, Yujin Hoshida, Amit G Singal, Adam Yopp, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency …

Pharmacodynamic Activity Of [18f]-Fluorthanatrace Poly(Adp-Ribose) Polymerase Positron Emission Tomography In Patients With Brca1/2-Mutated Breast Cancer Receiving Talazoparib, Lilie L Lin, Franklin Wong, Ruitao Lin, Timothy Yap, Jennifer K Litton

Faculty, Staff and Student Publications

Purpose: We tested the ability of [18F] fluorthanatrace (FTT), a radiolabeled analog of poly(ADP-ribose) polymerase (PARP)-1 inhibitors, to demonstrate target engagement on positron emission tomography (PET) scans from patients with newly diagnosed primary breast cancer receiving the PARP inhibitor (PARPi) talazoparib.

Methods: Seven patients with germline BRCA1/2 pathogenic variants underwent [18F]FTT PET-computed tomography scanning at baseline, and five underwent repeat scanning 14 days after talazoparib initiation. Maximum uptake on PET was quantified in the primary tumor, involved nodes, contralateral pectoralis muscle, and lumbar vertebra body level 3, and compared between the two time points.

Results: Blocking of [18F]FTT was observed …

Acute Myeloid Leukemia With Mast Cell Differentiation Is Characterized By Interstitial Mast Cells, Complex Karyotype, Do Hwan Kim, Sa A Wang, Wei Wang, Guilin Tang, Shaoying Li, C Cameron Yin, Pei Lin, Marina Konopleva, M James You, Roberto N Miranda, Xiaoqiong Wang, Qing Wei, L Jeffrey Medeiros, Jie Xu

Faculty, Staff and Student Publications

No abstract provided.

Novel Mutation Leading To Splice Donor Loss In A Conserved Site Of Dmd Gene Causes Duchenne Muscular Dystrophy With Cryptorchidism, Jianhai Chen, Yangying Jia, Jie Zhong, Kun Zhang, Hongzheng Dai, Guanglin He, Fuping Li, Li Zeng, Chuanzhu Fan, Huayan Xu

Faculty, Staff and Students Publications

Background: As one of the most common congenital abnormalities in male births, cryptorchidism has been found to have a polygenic aetiology according to previous studies of common variants. However, little is known about genetic predisposition of rare variants for cryptorchidism, since rare variants have larger effective size on diseases than common variants.

Methods: In this study, a cohort of 115 Chinese probands with cryptorchidism was analysed using whole-genome sequencing, alongside 19 parental controls and 2136 unaffected men. Additionally, CRISPR-Cas9 editing of a conserved variant was performed in a mouse model, with MRI screening used to observe the phenotype.

Results: In …

Clinical And Genomic Landscape Of Ras Mutations In Gynecologic Cancers, Ji Son, Yingao Zhang, Heather Lin, Oriol Mirallas, Pablo Alvarez Ballesteros, Mirella Nardo, Natalie Clark, R Tyler Hillman, Erick Campbell, Vijaykumar Holla, Amber M Johnson, Amadeo B Biter, Ying Yuan, Lauren P Cobb, David M Gershenson, Amir A Jazaeri, Karen H Lu, Pamela T Soliman, Shannon N Westin, Elizabeth D Euscher, Barrett C Lawson, Richard K Yang, Funda Meric-Bernstam, David S Hong

Faculty, Staff and Student Publications

Purpose: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications.

Experimental design: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan-Meier method, and multivariable analysis was performed using the Cox proportional hazard model.

Results: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and …

Chronic Eosinophilic Leukemia With A Novel Jak1 Mutation Responds Well To The Jak1/2 Inhibitor Ruxolitinib, Qing Wei, Jie Xu

Faculty, Staff and Student Publications

No abstract provided.

Ragopathies And The Rising Influence Of Raggtpases On Human Diseases, Irene Sambri, Marco Ferniani, Andrea Ballabio

Duncan NRI Faculty and Staff Publications

RagGTPases (Rags) play an essential role in the regulation of cell metabolism by controlling the activities of both mechanistic target of rapamycin complex 1 (mTORC1) and Transcription factor EB (TFEB). Several diseases, herein named ragopathies, are associated to Rags dysfunction. These diseases may be caused by mutations either in genes encoding the Rags, or in their upstream regulators. The resulting phenotypes may encompass a variety of clinical features such as cataract, kidney tubulopathy, dilated cardiomyopathy and several types of cancer. In this review, we focus on the key clinical, molecular and physio-pathological features of ragopathies, aiming to shed light on …

Genetic Diversity Of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation And Identifies Disease Models, Jun Wang, Meng Wang, Ala Moshiri, R Alan Harris, Muthuswamy Raveendran, Tracy Nguyen, Soohyun Kim, Laura Young, Keqing Wang, Roger Wiseman, David H O'Connor, Zach Johnson, Melween Martinez, Michael J Montague, Ken Sayers, Martha Lyke, Eric Vallender, Tim Stout, Yumei Li, Sara M Thomasy, Jeffrey Rogers, Rui Chen

Faculty, Staff and Students Publications

Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which …

Genomic Determinants Of Response And Resistance To Inotuzumab Ozogamicin In B-Cell All, Yaqi Zhao, Nicholas J Short, Hagop M Kantarjian, Ti-Cheng Chang, Pankaj S Ghate, Chunxu Qu, Walid Macaron, Nitin Jain, Beenu Thakral, Aaron H Phillips, Joseph Khoury, Guillermo Garcia-Manero, Wenchao Zhang, Yiping Fan, Hui Yang, Rebecca S Garris, Lewis F Nasr, Richard W Kriwacki, Kathryn G Roberts, Marina Konopleva, Elias J Jabbour, Charles G Mullighan

Faculty, Staff and Student Publications

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of the response and resistance to InO. Pre- and post-InO-treated patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO-relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation and destabilization) and epitope alteration. Two CD22 mutant cases were post-InO …

Exploring The Landscape Of Somatic Asxl2 Mutations In Myeloid Neoplasms: Frequency And Clinical Implications, Tareq Abuasab, Gautam Borthakur, Rashmi Kanagal-Shamanna, Lucia Masarova, Keyur Patel, Koichi Takahashi, Prithviraj Bose, John Villarreal, Sherry Pierce, Tapan Kadia, Guillermo Garcia-Manero, Nicholas J Short, Courtney Dinardo, Naval Daver, Farhad Ravandi, Hagop Kantarjian, Srdan Verstovsek, Musa Yilmaz

Faculty, Staff and Student Publications

No abstract provided.

Defining The Subset Of Mutations In Polymerase Epsilon (Pole) Associated With Loss-Of-Proofreading (Lop) Functionality, G Maddalena, F A Zeineddine, S Rivero-Hinojosa, V N Aushev, S Chowdhury, M A Zeineddine, A M Yousef, T A Yap, A C Einaggar, M C Liu, M White, M J Overman, S Kopetz, J P Shen

Faculty, Staff and Student Publications

No abstract provided.

Durable Objective Response To Lurbinectedin In Small Cell Bladder Cancer With Tp53 Mutation: A Molecular-Directed Strategy, Mohammad Jad Moussa, Jaanki Khandelwal, Nathaniel R Wilson, Sagar A Naik, Vivek Subbiah, Matthew T Campbell, Pavlos Msaouel, Parminder Singh, Omar Alhalabi

Faculty, Staff and Student Publications

Small cell bladder cancer (SCBC) is a rare and aggressive disease, often treated with platinum/etoposide-based chemotherapy. Key molecular drivers include the inactivation of onco-suppressor genes (TP53, RB1) and amplifications in proto-oncogenes (MYC). We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A genomic analysis of a metastatic biopsy prior to lurbinectedin initiation revealed a TP53 mutation and amplification of the cell cycle regulators E2F3 and MYCL. A repeat biopsy following …

Slow Proliferation Of Bap1-Deficient Uveal Melanoma Cells Is Associated With Reduced S6 Signaling And Resistance To Nutrient Stress, Vivian Chua, Melisa Lopez-Anton, Mizue Terai, Ryota Tanaka, Usman Baqai, Timothy J Purwin, Jelan I Haj, Francis J Waltrich, Isabella Trachtenberg, Kristine Luo, Rohith Tudi, Angela Jeon, Anna Han, Inna Chervoneva, Michael A Davies, Julio A Aguirre-Ghiso, Takami Sato, Andrew E Aplin

Faculty, Staff and Student Publications

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and …

Defining The Kras- And Erk-Dependent Transcriptome In Kras-Mutant Cancers, Jeffrey A Klomp, Jennifer E Klomp, Clint A Stalnecker, Kirsten L Bryant, A Cole Edwards, Kristina Drizyte-Miller, Priya S Hibshman, J Nathaniel Diehl, Ye S Lee, Alexis J Morales, Khalilah E Taylor, Sen Peng, Nhan L Tran, Laura E Herring, Alex W Prevatte, Natalie K Barker, Laura D Hover, Jill Hallin, Alexey Sorokin, Preeti Marie Kanikarla, Saikat Chowdhury, Oluwadara Coker, Hey Min Lee, Craig M Goodwin, Prson Gautam, Peter Olson, James G Christensen, John P Shen, Scott Kopetz, Lee M Graves, Kian-Huat Lim, Andrea Wang-Gillam, Krister Wennerberg, Adrienne D Cox, Channing J Der

Faculty, Staff and Student Publications

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and ERK-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges significantly from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome and other components of the cell cycle machinery as …

Piga Mutations And Glycosylphosphatidylinositol Anchor Dysregulation In Polyposis-Associated Duodenal Tumorigenesis, Elena Meuser, Kyle Chang, Angharad Walters, Joanna J Hurley, Hannah D West, Iain Perry, Matthew Mort, Laura Reyes-Uribe, Rebekah Truscott, Nicholas Jones, Rachel Lawrence, Gareth Jenkins, Peter Giles, Sunil Dolwani, Bilal Al-Sarireh, Neil Hawkes, Emma Short, Geraint T Williams, Melissa W Taggart, Kim Luetchford, Patrick M Lynch, Diantha Terlouw, Maartje Nielsen, Sarah-Jane Walton, Andrew Latchford, Susan K Clark, Julian R Sampson, Eduardo Vilar, Laura E Thomas

Faculty, Staff and Student Publications

The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumors and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyzes the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of …

Efficacy And Safety Of Adagrasib Plus Cetuximab In Patients With Krasg12c-Mutated Metastatic Colorectal Cancer, Rona Yaeger, Nataliya V Uboha, Meredith S Pelster, Tanios S Bekaii-Saab, Minal Barve, Joel Saltzman, Joshua K Sabari, Julio A Peguero, Andrew Scott Paulson, Pasi A Jänne, Marcia Cruz-Correa, Kenna Anderes, Karen Velastegui, Xiaohong Yan, Hirak Der-Torossian, Samuel J Klempner, Scott E Kopetz

Faculty, Staff and Student Publications

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2-7.6). Median progression-free survival was 6.9 months …

Rewiring The Sex-Determination Pathway During The Evolution Of Self-Fertility., Yongquan Shen, Shin-Yi Lin, Jonathan Harbin, Richa Amin, Allison Vassalotti, Joseph Romanowski, Emily Schmidt, Alexis Tierney, Ronald E Ellis

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Although evolution is driven by changes in how regulatory pathways control development, we know little about the molecular details underlying these transitions. The TRA-2 domain that mediates contact with TRA-1 is conserved in Caenorhabditis. By comparing the interaction of these proteins in two species, we identified a striking change in how sexual development is controlled. Identical mutations in this domain promote oogenesis in Caenorhabditis elegans but promote spermatogenesis in Caenorhabditis briggsae. Furthermore, the effects of these mutations involve the male-promoting gene fem-3 in C. elegans but are independent of fem-3 in C. briggsae. Finally, reciprocal mutations in these genes show …

Plasmacytoid Urothelial Carcinoma Of The Urinary Bladder-A Clinicopathological And Molecular Analysis Of 52 Cases, Lan Zheng, Hui Chen, Jianping Zhao, Sinchita Roy-Chowdhuri, Ashish M Kamat, Omar Alhalabi, Jianjun Gao, Arlene Siefker-Radtke, Donna E Hansel, Bogdan Czerniak, Charles C Guo

Faculty, Staff and Student Publications

Plasmacytoid urothelial carcinoma (UC) is a rare histologic subtype of bladder cancer that is associated with an aggressive clinical behavior. We analyzed the clinicopathologic and molecular features of plasmacytoid UC in 52 patients from a single institute. The patients included 44 men and 8 women, with a mean age of 64 years (range, 41-91 years). All bladder cancers were high-grade UC, and plasmacytoid component accounted for a mean of 47% of bladder tumors (range, 5-100%). Distinct gene mutations were found in most plasmacytoid UCs (n = 49); the most common mutations were TP53 (n = 30), followed by TERT (n …

Expanding The Phenotype Of Ppp1r21-Related Neurodevelopmental Disorder, Mohammed Almannai, Dana Marafi, Maha S Zaki, Reza Maroofian, Stephanie Efthymiou, Nebal Waill Saadi, Bilal Filimban, Hormos Salimi Dafsari, Fatima Rahman, Shazia Maqbool, Eissa Faqeih, Fuad Al Mutairi, Hind Alsharhan, Omar Abdelaty, Saadoun Bin-Hasan, Ruizhi Duan, Mahmoud M Noureldeen, Alaa Alqattan, Henry Houlden, Jill V Hunter, Jennifer E Posey, James R Lupski, Ayman W El-Hattab

Faculty, Staff and Students Publications

PPP1R21 encodes for a conserved protein that is involved in endosomal maturation. Biallelic pathogenic variants in PPP1R21 have been associated with a syndromic neurodevelopmental disorder from studying 13 affected individuals. In this report, we present 11 additional individuals from nine unrelated families and their clinical, radiological, and molecular findings. We identified eight different variants in PPP1R21, of which six were novel variants. Global developmental delay and hypotonia are neurological features that were observed in all individuals. There is also a similar pattern of dysmorphic features with coarse faces as a gestalt observed in several individuals. Common findings in 75% of …