Emily G. Shuldiner

National Institute of Arthritis and Musculoskeletal and Skin Diseases

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Laura Andrejka

Stanford University

Monte M. Winslow

Stanford University

Dmitri A. Petrov

Stanford University

Min K. Tsai

Stanford University

Rui Tang

Nanjing Medical University

Hongchen Cai

Stanford University

Nicholas W. Hughes

Stanford University

Christopher W. Murray

Stanford University

Emily L. Ashkin

Stanford University

Su Kit Chew

The Francis Crick Institute

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Stanford University

Stratford University

National Institute of Arthritis and Musculoskeletal and Skin Diseases

University College London

National Institutes of Health

Pediatrics and Genetics

Cincinnati Children's Hospital Medical Center

Harvard University

Istituto Giannina Gaslini

National Human Genome Research Institute

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Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications

Annals of the Rheumatic Diseases (2016)

Michael J. Ombrello Victoria Arthur Elaine F. Remmers Anne Hinks Ioanna Tachmazidou

Objectives Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. Methods We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. Results The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. Conclusions The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.

Genome-wide Association Study

Genetic architecture

10.1136/annrheumdis-2016-210324

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Functional mapping of epigenetic regulators uncovers coordinated tumor suppression by the HBO1 and MLL1 complexes

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Yuning J. Tang Haiqing Xu Nicholas W. Hughes Samuel H. Kim Paloma Ruiz

Abstract Epigenetic dysregulation is widespread in cancer. However, the specific epigenetic regulators and the processes they control to drive cancer phenotypes are poorly understood. Here, we employed a novel, scalable and high-throughput in vivo method to perform iterative functional screens of over 250 epigenetic regulatory genes within autochthonous oncogenic KRAS-driven lung tumors. We identified multiple novel epigenetic tumor suppressor and tumor dependency genes. We show that a specific HBO1 complex and the MLL1 complex are among the most impactful tumor suppressive epigenetic regulators in lung. The histone modifications generated by the HBO1 complex are frequently absent or reduced in human lung adenocarcinomas. The HBO1 and MLL1 complexes regulate chromatin accessibility of shared genomic regions, lineage fidelity and the expression of canonical tumor suppressor genes. The HBO1 and MLL1 complexes are epistatic during lung tumorigenesis, and their functional correlation is conserved in human cancer cell lines. Together, these results demonstrate the value of quantitative methods to generate a phenotypic roadmap of epigenetic regulatory genes in tumorigenesis in vivo .

10.1101/2024.08.19.607671

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Multiplexed screens identify RAS paralogs HRAS and NRAS as suppressors of KRAS-driven lung cancer growth

Figshare (2023)

Rui Tang Emily G. Shuldiner Marcus R. Kelly Christopher W. Murray Jess D. Hebert

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HRAS

10.6084/m9.figshare.21383871

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IL1RN Variation Influences both Disease Susceptibility and Response to Human Recombinant IL-1RA Therapy in Systemic Juvenile Idiopathic Arthritis

VL Arthur Emily G. Shuldiner EF Remmers Anne Hinks AA Grom

OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (sJIA) susceptibility loci identified by candidate gene studies demonstrated association with sJIA in the largest study population assembled to date. METHODS: Single nucleotide polymorphisms (SNPs) from 11 previously reported sJIA risk loci were examined for association in 9 populations, including 770 sJIA cases and 6947 control subjects. The effect of sJIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from lymphoblastoid cell lines (LCL) of 373 European 1000 Genomes Project subjects. The relationship between sJIA-associated SNPs and response to anakinra treatment was evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association of the 26 SNPs previously reported as sJIA-associated. Expanded analysis of the regions containing the 26 SNPs revealed only one significant association, the promoter region of IL1RN (p<1E-4). sJIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between sJIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with non-response to anakinra therapy (OR 28.7 [3.2, 255.8]). CONCLUSION: IL1RN was the only candidate locus associated with sJIA in our study. The implicated SNPs are among the strongest known determinants of IL1RN and IL1RA levels, linking low expression with increased sJIA risk. Homozygous high expression alleles predicted non-response to anakinra therapy, nominating them as candidate biomarkers to guide sJIA treatment. This is an important first step towards the personalized treatment of sJIA. This article is protected by copyright. All rights reserved.

Genome-wide Association Study

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Aging represses lung tumorigenesis and alters tumor suppression

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Emily G. Shuldiner Saswati Karmakar Min K. Tsai Jess D. Hebert Yuning J. Tang

Most cancers are diagnosed in persons over the age of sixty, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation - widely understood to contribute to cancer risk - it is also associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many, but not all, tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K/AKT pathway, weakened to a disproportionate extent. Single-cell transcriptomic analysis revealed that neoplastic cells from tumors in old mice retain many age-related transcriptomic changes, showing that age has an enduring impact that persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings suggest that the relationship between age and lung cancer incidence may reflect an integration of the competing effects of driver mutation accumulation and tumor suppressive effects of aging.

Tumor initiation

Senescence

Neoplastic transformation

10.1101/2024.05.28.596319

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Citations (6)

Survival of the friendliest

TheScienceBreaker (2017)

Bridgett M. vonHoldt Emily G. Shuldiner Monique A. R. Udell

10.25250/thescbr.brk075

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Table S1 from A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS–Driven Lung Cancer

Hongchen Cai Su Kit Chew Chuan Li Min K. Tsai Laura Andrejka

Table S1. Mutation data of the genes that we selected for investigation.

Table (database)

10.1158/2159-8290.22540426

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High-Throughput Identification, Modeling, and Analysis of Cancer Driver Genes In Vivo

Cold Spring Harbor Perspectives in Medicine (2023)

Yuning J. Tang Emily G. Shuldiner Saswati Karmakar Monte M. Winslow

Yuning J. Tang1, Emily G. Shuldiner2, Saswati Karmakar1 and Monte M. Winslow1,3 1Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA 2Department of Biology, Stanford University, Stanford, California 94305, USA 3Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA Correspondence: mwinslow{at}stanford.edu

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Cancer genetics

10.1101/cshperspect.a041382

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Data from A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS–Driven Lung Cancer

Hongchen Cai Su Kit Chew Chuan Li Min K. Tsai Laura Andrejka

<div>AbstractCancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS–driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression.Significance:Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS–driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative in vivo genetic analyses in autochthonous cancer models.This article is highlighted in the In This Issue feature, p. 1601</div>

Tumor initiation

Tumor progression

10.1158/2159-8290.c.6549376

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Table S2 from A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS–Driven Lung Cancer

Hongchen Cai Su Kit Chew Chuan Li Min K. Tsai Laura Andrejka

Table S2. The information of sgRNA vectors in the high content Lenti-sgTS102/Cre pool.

Table (database)

Table of contents

10.1158/2159-8290.22540423.v1

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