Demo Faculty

211 articles

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Oct 2018 • Nature medicine

Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response

Peng Jiang, Shengqing Gu, Deng Pan, Jingxin Fu, Avinash Sahu, Xihao Hu, Ziyi Li, Nicole Traugh, Xia Bu, Bo Li, Jun Liu, Gordon J Freeman, Myles A Brown, Kai W Wucherpfennig, X Shirley Liu

Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line …

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Sep 2018 • Journal of Vision

Creating correct blur and its effect on accommodation

Steven A Cholewiak, Gordon D Love, Martin S Banks

Blur occurs naturally when the eye is focused at one distance and an object is presented at another distance. Computer-graphics engineers and vision scientists often wish to create display images that reproduce such depth-dependent blur, but their methods are incorrect for that purpose. They take into account the scene geometry, pupil size, and focal distances, but do not properly take into account the optical aberrations of the human eye. We developed a method that, by incorporating the viewer's optics, yields displayed images that produce retinal images close to the ones that occur in natural viewing. We concentrated on the effects of defocus, chromatic aberration, astigmatism, and spherical aberration and evaluated their effectiveness by conducting experiments in which we attempted to drive the eye's focusing response (accommodation) through the rendering of these aberrations. We found that accommodation is not driven at all by conventional rendering methods, but that it is driven surprisingly quickly and accurately by our method with defocus and chromatic aberration incorporated. We found some effect of astigmatism but none of spherical aberration. We discuss how the rendering approach can be used in vision science experiments and in the development of ophthalmic/optometric devices and augmented-and virtual-reality displays.

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Sep 2018 • Bioinformatics

SequencEnG: an Interactive Knowledge Base of Sequencing Techniques

Yi Zhang, Mohith Manjunath, Yeonsung Kim, Joerg Heintz, Jun S Song

summary Next-generation sequencing (NGS) techniques are revolutionizing biomedical research by providing powerful methods for generating genomic and epigenomic profiles. The rapid progress is posing an acute challenge to students and researchers to stay acquainted with the numerous available methods. We have developed an interactive online educational resource called Sequencing Techniques Engine for Genomics (SequencEnG) to provide a tree-structured knowledge base of 66 different sequencing techniques and step-by-step NGS data analysis pipelines comparing popular tools. SequencEnG is designed to facilitate barrier-free learning of current NGS techniques and provides a user-friendly interface for searching through experimental and analysis methods. Availability and implementation SequencEnG is part of the project Knowledge Engine for Genomics …

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Sep 2018 • Journal of Vision

Driving accommodation using simulated higher-order aberrations

Steven Cholewiak, Gordon Love, Martin Banks

The purpose of accommodation is to minimize blur. Defocus blur is the major source of blurring in the retinal image, but defocus blur itself cannot tell the eye if it is focused too near or too far. When the human eye is shown real blur, accommodation always changes in the correct direction without searching, so the visual system can somehow determine the sign of defocus. Potential signals for the sign include temporal fluctuations of accommodation (eg, microfluctuations), chromatic aberration, and higher-order aberrations (HOAs). We investigated whether simulated HOAs—specifically, astigmatism and spherical aberration—provide the needed sign information to drive accommodation in the right direction. Measurable astigmatism occurs in most people; its magnitude and axis varies across individuals. The point-spread function (PSF) of a defocused astigmatic eye is elliptical with the major axis in one direction when …

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Sep 2018 • Journal of Vision

ChromaBlur: Rendering natural chromatic aberration drives accommodation effectively

Martin Banks, Steven Cholewiak, Gordon Love

Retinal-image blur occurs when the eye is focused at one distance and an object is at another. Vision scientists and computer-graphics engineers often wish to create images that reproduce such depth-dependent blur, but their method is incorrect because it does not incorporate the human eye's optical aberrations. We developed a rendering method that, by incorporating these aberrations, creates displayed images that produce more natural retinal images. Here we concentrate on one aberration: longitudinal chromatic aberration (LCA). LCA creates different chromatic effects in the retinal image for objects farther vs nearer than current focus. We asked whether one can drive eye focus (accommodation) by incorporating LCA into the rendering of objects meant to appear farther or nearer than current focus. Observers viewed textured planes monocularly in three conditions: 1) Real Change in which stimulus focal …

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Aug 2018 • Interface focus

Colour, contours, shading and shape: flow interactions reveal anchor neighbourhoods

Benjamin Kunsberg, Daniel Holtmann-Rice, Emma Alexander, Steven Cholewiak, Roland Fleming, Steven W Zucker

Two dilemmas arise in inferring shape information from shading. First, depending on the rendering physics, images can change significantly with (even) small changes in lighting or viewpoint, while the percept frequently does not. Second, brightness variations can be induced by material effects—such as pigmentation—as well as by shading effects. Improperly interpreted, material effects would confound shading effects. We show how these dilemmas are coupled by reviewing recent developments in shape inference together with a role for colour in separating material from shading effects. Aspects of both are represented in a common geometric (flow) framework, and novel displays of hue/shape interaction demonstrate a global effect with interactions limited to localized regions. Not all parts of an image are perceptually equal; shape percepts appear to be constructed from image anchor regions.

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Aug 2018 • Blood, The Journal of the American Society of Hematology

Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell–rich and exhausted T-effector microenvironment

Fathima Zumla Cader, Ron CJ Schackmann, Xihao Hu, Kirsty Wienand, Robert Redd, Bjoern Chapuy, Jing Ouyang, Nicole Paul, Evisa Gjini, Mikel Lipschitz, Philippe Armand, David Wu, Jonathan R Fromm, Donna Neuberg, X Shirley Liu, Scott J Rodig, Margaret A Shipp

In classical Hodgkin lymphoma (cHL), the host antitumor immune response is ineffective. Hodgkin Reed-Sternberg (HRS) cells have multifaceted mechanisms to evade the immune system, including 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) genetic alterations, overexpression of PD-1 ligands, and associated T-cell exhaustion and additional structural bases of aberrant antigen presentation. The clinical success of PD-1 blockade in cHL suggests that the tumor microenvironment (TME) contains reversibly exhausted T effector cells (Teffs). However, durable responses are observed in patients with β2-microglobulin/major histocompatibility complex (MHC) class I loss on HRS cells, raising the possibility of non-CD8+ T cell–mediated mechanisms of efficacy of PD-1 blockade. These observations highlight the need for a detailed analysis of the cHL TME. Using a customized time-of-flight mass cytometry panel, we …

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Jul 2018 • Annual Review of Biomedical Data Science 1, 1-27, 2018

Big Data Approaches for Modeling Response and Resistance to Cancer Drugs

Peng Jiang, William R Sellers, X Shirley Liu

Despite significant progress in cancer research, current standard-of-care drugs fail to cure many types of cancers. Hence, there is an urgent need to identify better predictive biomarkers and treatment regimes. Conventionally, insights from hypothesis-driven studies are the primary force for cancer biology and therapeutic discoveries. Recently, the rapid growth of big data resources, catalyzed by breakthroughs in high-throughput technologies, has resulted in a paradigm shift in cancer therapeutic research. The combination of computational methods and genomics data has led to several successful clinical applications. In this review, we focus on recent advances in data-driven methods to model anticancer drug efficacy, and we present the challenges and opportunities for data science in cancer therapeutic research.

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Jul 2018 • Proceedings of the National Academy of Sciences

Estrogen-regulated feedback loop limits the efficacy of estrogen receptor–targeted breast cancer therapy

Tengfei Xiao, Wei Li, Xiaoqing Wang, Han Xu, Jixin Yang, Qiu Wu, Ying Huang, Joseph Geradts, Peng Jiang, Teng Fei, David Chi, Chongzhi Zang, Qi Liao, Jonathan Rennhack, Eran Andrechek, Nanlin Li, Simone Detre, Mitchell Dowsett, Rinath M Jeselsohn, X Shirley Liu, Myles Brown

Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER+) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER+ breast cancer. At low CSK levels, as is the case in patients with ER+ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer …

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Jul 2018 • European journal of immunology

FACS single cell index sorting is highly reliable and determines immune phenotypes of clonally expanded T cells

Livius Penter, Kerstin Dietze, Lars Bullinger, Jörg Westermann, Hans‐Peter Rahn, Leo Hansmann

FACS index sorting allows the isolation of single cells with retrospective identification of each single cell's high‐dimensional immune phenotype. We experimentally determine the error rate of index sorting and combine the technology with T cell receptor sequencing to identify clonal T cell expansion in aplastic anemia bone marrow as an example.

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Jul 2018 • Cancer Research 78 (13 Supplement), 1220-1220, 2018

Integrative genomic analysis discovers the causative regulatory mechanisms of a breast cancer-associated genetic variant

Yi Zhang, Mohith Manjunath, Shilu Zhang, Deborah Chasman, Sushmita Roy, Jun S Song

Genome-wide association studies (GWAS) have identified genetic variants that may significantly modulate breast cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely unknown; often, it is not even clear whether the GWAS variants are functional themselves or just genetically linked to other functional variants. We here provide an integrated method for identifying functional regulatory variants associated with breast cancer and their target genes by combining the analyses of expression quantitative trait loci (eQTL), a modified version of allele-specific expression (ASE) systematically utilizing haplotype information, transcription factor (TF) binding preference, and epigenetic information. Application of our method to the breast cancer susceptibility region in 5p12 demonstrates that the GWAS risk allele rs4415084-T is correlated with higher expression levels of the …

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Jul 2018 • Cancer Research 78 (13_Supplement), 4679-4679, 2018

Rectal cancer-infiltrating T cells show clonal expansion associated with spatially restricted tolerogenic phenotypes

Livius Penter, Kerstin Dietze, Felix Aigner, Lars Bullinger, Thomas Blankenstein, Leo Hansmann

T cell infiltration correlates with prognosis and outcome in colorectal cancer regardless of the tumor stage. However, data on clonal expansion, phenotypes, functions, and spatial distribution of tumor-infiltrating T cells (TILs) are limited.We hypothesized that subsets of clonally expanded rectal cancer-associated T cells are specifically recruited into the tumor and show characteristic phenotypes and functions.Paired TILs and T cells from adjacent unaffected mucosa were isolated from five treatment-naïve rectal cancer patients. Although T cell immune phenotypes were heterogeneous, the frequencies of CD38+, PD-1+, and TIM-3+ cells were significantly higher in CD8+ TILs when compared to T cells from unaffected mucosa (p < 0.05). To track clonal expansion and phenotypes at the single cell level, we combined 13-parameter FACS single cell index sorting with next generation T cell receptor (TCR) and phenotype …

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Jul 2018 • American Association for Cancer Research

Single-cell mass cytometry of classical Hodgkin lymphoma defines an exhausted and immunosuppressive microenvironment

Fathima Z Cader, Ron C Schackmann, Xihao Hu, Kirsty Wienand, Robert A Redd, Bjoern Chapuy, Jing Ouyang, Nicole E Paul, Evisa Gjini, Mikel Lipschitz, Laura M Selfors, Philippe Armand, David Wu, Jonathan R Fromm, Donna Neuberg, Xiaole S Liu, Scott J Rodig, Margaret A Shipp

Background: In classical Hodgkin lymphoma (cHL), the rare malignant Hodgkin Reed-Sternberg (HRS) cells are surrounded by an inflammatory infiltrate. Yet, the host anti-tumor immune response is ineffective. HRS cells have multifaceted mechanisms to evade the immune system including 9p24.1/PD-L1/PD-L2 genetic alterations leading to overexpression of PD-1 ligands and subsequent T cell exhaustion, aberrant antigen presentation and modulation of the tumor microenvironment (TME).The clinical success of PD-1 blockade in cHL suggests the TME contains reversibly exhausted T-effectors (Teff). Paradoxically, durable responses are observed in patients with β2M/MHC class I loss on HRS cells, raising the possibility of non-CD8+ mediated mechanisms of efficacy of PD-1 blockade. For this reason, we sought to characterize HRS cells and the surrounding TME.Methods: Using CyTOF technology, we evaluated …

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Jun 2018 • Bioinformatics

Improved design and analysis of CRISPR knockout screens

Chen-Hao Chen, Tengfei Xiao, Han Xu, Peng Jiang, Clifford A Meyer, Wei Li, Myles Brown, X Shirley Liu

MotivationGenome-wide clustered, regularly interspaced, short palindromic repeat (CRISPR)-Cas9 screen has been widely used to interrogate gene functions. However, the rules to design better libraries beg further refinement.ResultsWe found single guide RNA (sgRNA) outliers are characterized by higher G-nucleotide counts, especially in regions distal from the PAM motif and are associated with stronger off-target activities. Furthermore, using non-targeting sgRNAs as negative controls lead to strong bias, which can be mitigated by using sgRNAs targeting multiple ‘safe harbor’ regions. Custom-designed screens confirmed our findings and further revealed that 19 nt sgRNAs consistently gave the best signal-to-noise ratio. Collectively, our analysis motivated the design of a new genome-wide CRISPR/Cas9 screen library and uncovered some intriguing properties of the …

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May 2018 • PeerJ Computer Science

ClusterEnG: an interactive educational web resource for clustering and visualizing high-dimensional data

Mohith Manjunath, Yi Zhang, Yeonsung Kim, Steve H Yeo, Omar Sobh, Nathan Russell, Christian Followell, Colleen Bushell, Umberto Ravaioli, Jun S Song

BackgroundClustering is one of the most common techniques in data analysis and seeks to group together data points that are similar in some measure. Although there are many computer programs available for performing clustering, a single web resource that provides several state-of-the-art clustering methods, interactive visualizations and evaluation of clustering results is lacking.MethodsClusterEnG (acronym for Clustering Engine for Genomics) provides a web interface for clustering data and interactive visualizations including 3D views, data selection and zoom features. Eighteen clustering validation measures are also presented to aid the user in selecting a suitable algorithm for their dataset. ClusterEnG also aims at educating the user about the similarities and differences between various clustering algorithms and provides tutorials that demonstrate potential pitfalls of each algorithm.ConclusionsThe web resource will be particularly useful to scientists who are not conversant with computing but want to understand the structure of their data in an intuitive manner. The validation measures facilitate the process of choosing a suitable clustering algorithm among the available options. ClusterEnG is part of a bigger project called KnowEnG (Knowledge Engine for Genomics) and is available at http://education. knoweng. org/clustereng.BackgroundClustering is one of the most powerful and widely used analysis techniques for discovering structure in large datasets by grouping data points that are similar according to some measure. Several programming languages such as R (R Core Team, 2015) and Python (Pedregosa et al., 2011) offer libraries …

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Apr 2018 • Cancer research

Integrative Genomic Analysis Predicts Causative Cis-Regulatory Mechanisms of the Breast Cancer–Associated Genetic Variant rs4415084Regulatory Genomics of GWAS SNPs

Yi Zhang, Mohith Manjunath, Shilu Zhang, Deborah Chasman, Sushmita Roy, Jun S Song

Previous genome-wide association studies (GWAS) have identified several common genetic variants that may significantly modulate cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely unknown; it is often not clear whether discovered variants are themselves functional or merely genetically linked to other functional variants. Here, we provide an integrated method for identifying functional regulatory variants associated with cancer and their target genes by combining analyses of expression quantitative trait loci, a modified version of allele-specific expression that systematically utilizes haplotype information, transcription factor (TF)–binding preference, and epigenetic information. Application of our method to a breast cancer susceptibility region in 5p12 demonstrates that the risk allele rs4415084-T correlates with higher expression levels of the protein-coding …

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Mar 2018 • Cell systems

Genome-Scale Signatures of Gene Interaction from Compound Screens Predict Clinical Efficacy of Targeted Cancer Therapies

Peng Jiang, Winston Lee, Xujuan Li, Carl Johnson, Jun S Liu, Myles Brown, Jon Christopher Aster, X Shirley Liu

Identifying reliable drug response biomarkers is a significant challenge in cancer research. We present computational analysis of resistance (CARE), a computational method focused on targeted therapies, to infer genome-wide transcriptomic signatures of drug efficacy from cell line compound screens. CARE outputs genome-scale scores to measure how the drug target gene interacts with other genes to affect the inhibitor efficacy in the compound screens. Such statistical interactions between drug targets and other genes were not considered in previous studies but are critical in identifying predictive biomarkers. When evaluated using transcriptome data from clinical studies, CARE can predict the therapy outcome better than signatures from other computational methods and genomics experiments. Moreover, the CARE signatures for the PLX4720 BRAF inhibitor are associated with an anti-programmed death 1 …

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Mar 2018 • Oncogenesis

Expression of lncRNA MIR222HG co-transcribed from the miR-221/222 gene promoter facilitates the development of castration-resistant prostate cancer

Tong Sun, Shin-Yi Du, Joshua Armenia, Fangfang Qu, Jingyu Fan, Xiaodong Wang, Teng Fei, Kazumasa Komura, Shirley X Liu, Gwo-Shu Mary Lee, Philip W Kantoff

Mechanisms by which non-coding RNAs contribute to the progression of hormone-sensitive prostate cancer (PCa)(HSPC) to castration-resistant PCa (CRPC) remain largely unknown. We previously showed that microRNA-221/222 is up-regulated in CRPC and plays a critical role in modulating androgen receptor function during CRPC development. With further investigation, we characterized a putative promoter region located 23.3 kb upstream of the miR-221/222 gene, and this promoter is differentially activated in CRPC LNCaP-Abl cells, leading to the up-regulation of miR-221/222. Upon promoter activation, a set of polyadenylated long non-coding RNA (lncRNA) MIR222HGs was transcribed from this promoter region. Over-expression of these MIR222HGs increased androgen-independent cell growth and repressed the expression of androgen receptor-regulated dihydrotestosterone (DHT)-induced KLK3 …

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Feb 2018 • Science

A major chromatin regulator determines resistance of tumor cells to T cell–mediated killing

Deng Pan, Aya Kobayashi, Peng Jiang, Lucas Ferrari de Andrade, Rong En Tay, Adrienne M Luoma, Daphne Tsoucas, Xintao Qiu, Klothilda Lim, Prakash Rao, Henry W Long, Guo-Cheng Yuan, John Doench, Myles Brown, X Shirley Liu, Kai W Wucherpfennig

Many human cancers are resistant to immunotherapy, for reasons that are poorly understood. We used a genome-scale CRISPR-Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of &gt;100 genes—including Pbrm1, Arid2, and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex—sensitized mouse B16F10 melanoma cells to killing by T cells. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by …

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Feb 2018 • Cancer cell

Allele-specific chromatin recruitment and therapeutic vulnerabilities of ESR1 activating mutations

Rinath Jeselsohn, Johann S Bergholz, Matthew Pun, MacIntosh Cornwell, Weihan Liu, Agostina Nardone, Tengfei Xiao, Wei Li, Xintao Qiu, Gilles Buchwalter, Ariel Feiglin, Kayley Abell-Hart, Teng Fei, Prakash Rao, Henry Long, Nicholas Kwiatkowski, Tinghu Zhang, Nathanael Gray, Diane Melchers, Rene Houtman, X Shirley Liu, Ofir Cohen, Nikhil Wagle, Eric P Winer, Jean Zhao, Myles Brown

Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER+) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. Analysis of the genome-wide ER binding sites identified mutant ER unique recruitment mediating the allele-specific transcriptional program. Genetic screens identified genes that are essential for the ligand-independent growth driven by the mutants. These studies provide insights into the mechanism of endocrine therapy resistance engendered by ER mutations and potential therapeutic …

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Jan 2018 • bioRxiv

Can cancer GWAS variants modulate immune cells in the tumor microenvironment?

Yi Zhang, Mohith Manjunath, Jialu Yan, Brittany A Baur, Shilu Zhang, Sushmita Roy, Jun S Song

Genome-wide association studies (GWAS) have hitherto identified several genetic variants associated with cancer susceptibility, but the molecular functions of these risk modulators remain largely uncharacterized. Recent studies have begun to uncover the regulatory potential of non-coding GWAS SNPs by using epigenetic information in corresponding cancer cell types and matched normal tissues. However, this approach does not explore the potential effect of risk germline variants on other important cell types that constitute the microenvironment of tumor or its precursor. This paper presents evidence that the breast cancer-associated variant rs3903072 may regulate the expression of CTSW in tumor infiltrating lymphocytes. CTSW is a candidate tumor-suppressor gene, with expression highly specific to immune cells and also positively correlated with breast cancer patient survival. Integrative analyses suggest a putative causative variant in a GWAS-linked enhancer in lymphocytes that loops to the 3’ end of CTSW through three-dimensional chromatin interaction. Our work thus poses the possibility that a cancer-associated genetic variant might regulate a gene not only in the cell of cancer origin, but also in immune cells in the microenvironment, thereby modulating the immune surveillance by T lymphocytes and natural killer cells and affecting the clearing of early cancer initiating cells.

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