Medical Specialties Commons^™

Lapatinib And Poziotinib Overcome Abcb1-Mediated Paclitaxel Resistance In Ovarian Cancer, J. Robert Mccorkle, Justin W. Gorski, Jinpeng Liu, Mckayla J. Riggs, Anthony B. Mcdowell Jr., Nan Lin, Chi Wang, Frederick R. Ueland, Jill M. Kolesar

Markey Cancer Center Faculty Publications

Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We established in vitro paclitaxel-resistant ovarian cancer cell line and organoid models. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing. We manipulated candidate genes associated with paclitaxel resistance using siRNA or small molecule inhibitors, and then screened the cells for paclitaxel sensitivity using cell viability assays. …

Clinical Outcomes Of Molecular Tumor Boards: A Systematic Review, Kara L. Larson, Bin Huang, Heidi L. Weiss, Pamela C. Hull, Philip M. Westgate, Rachel W. Miller, Susanne M. Arnold, Jill M. Kolesar

Markey Cancer Center Faculty Publications

PURPOSE: We conducted this systematic review to evaluate the clinical outcomes associated with molecular tumor board (MTB) review in patients with cancer.

METHODS: A systematic search of PubMed was performed to identify studies reporting clinical outcomes in patients with cancer who were reviewed by an MTB. To be included, studies had to report clinical outcomes, including clinical benefit, response, progression-free survival, or overall survival. Two reviewers independently selected studies and assessed quality with the Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group or the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies depending on the type …

Pi3k/Mtor Dual Inhibitor Pf-04691502 Is A Schedule-Dependent Radiosensitizer For Gastroenteropancreatic Neuroendocrine Tumors, Zeta Chow, Jeremy Johnson, Aman Chauhan, Tadahide Izumi, Michael Cavnar, Heidi L. Weiss, Courtney M. Townsend Jr., Lowell B. Anthony, Carrigan Wasilchenko, Matthew L. Melton, Jörg Schrader, B. Mark Evers, Piotr G. Rychahou

Markey Cancer Center Faculty Publications

Patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor overall prognosis despite chemotherapy and radiotherapy (e.g., peptide receptor radionuclide therapy (PRRT)). Better treatment options are needed to improve disease regression and patient survival. The purpose of this study was to examine a new treatment strategy by combining PI3K/mTOR dual inhibition and radiotherapy. First, we assessed the efficacy of two PI3K/mTOR dual inhibitors, PF-04691502 and PKI-402, to inhibit pAkt and increase apoptosis in NET cell lines (BON and QGP-1) and patient-derived tumor spheroids as single agents or combined with radiotherapy (XRT). Treatment with PF-04691502 decreased pAkt (Ser473) expression for up …

Myocarditis Concurrent With Sweet Syndrome: A Presentation Of Acute Myeloid Leukemia, Christopher G. Burkeen, David Pottinger, Chaitanya Iragavarapu, Reshma Ramlal, Gerhard C. Hildebrandt

Markey Cancer Center Faculty Publications

Acute myeloid leukemia (AML) is the most common acute leukemia in American adults and portends a poor prognosis if untreated. Commonly, AML presents with symptoms related to concurrent leukopenia, anemia, or thrombocytopenia; however, due to its ability to affect many organ systems in the body, AML can have a highly varied clinical presentation. One such presentation is myocarditis, which is a rarely reported manifestation of AML. Myocarditis can have a varied clinical picture and often requires exclusion of other causes of cardiac dysfunction. Sweet syndrome, also known as acute febrile neutrophilic dermatosis, is another presentation of AML; however, it is …

The Mwtab Python Library For Restful Access And Enhanced Quality Control, Deposition, And Curation Of The Metabolomics Workbench Data Repository, Christian D. Powell, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

The Metabolomics Workbench (MW) is a public scientific data repository consisting of experimental data and metadata from metabolomics studies collected with mass spectroscopy (MS) and nuclear magnetic resonance (NMR) analyses. MW has been constantly evolving; updating its ‘mwTab’ text file format, adding a JavaScript Object Notation (JSON) file format, implementing a REpresentational State Transfer (REST) interface, and nearly quadrupling the number of datasets hosted on the repository within the last three years. In order to keep up with the quickly evolving state of the MW repository, the ‘mwtab’ Python library and package have been continuously updated to mirror the changes …

Genome-Wide Association Meta-Analysis Identifies Pleiotropic Risk Loci For Aerodigestive Squamous Cell Cancers, Corina Lesseur, Aida Ferreiro-Iglesias, James D. Mckay, Yohan Bossé, Mattias Johansson, Valerie Gaborieau, Maria Teresa Landi, David C. Christiani, Neil C. Caporaso, Stig E. Bojesen, Christopher I. Amos, Sanjay Shete, Geoffrey Liu, Gadi Rennert, Demetrius Albanes, Melinda C. Aldrich, Adonina Tardon, Chu Chen, Liloglou Triantafillos, John K. Field, Susanne Arnold

Markey Cancer Center Faculty Publications

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (P_meta< 5x10^-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown …

A New Efficient Method To Detect Genetic Interactions For Lung Cancer Gwas, Jennifer Luyapan, Xuemei Ji, Siting Li, Xiangjun Xiao, Dakai Zhu, Eric J. Duell, David C. Christiani, Matthew B. Schabath, Susanne M. Arnold, Shanbeh Zienolddiny, Hans Brunnström, Olle Melander, Mark D. Thornquist, Todd A. Mackenzie, Christopher I. Amos, Jiang Gui

Markey Cancer Center Faculty Publications

BACKGROUND: Genome-wide association studies (GWAS) have proven successful in predicting genetic risk of disease using single-locus models; however, identifying single nucleotide polymorphism (SNP) interactions at the genome-wide scale is limited due to computational and statistical challenges. We addressed the computational burden encountered when detecting SNP interactions for survival analysis, such as age of disease-onset. To confront this problem, we developed a novel algorithm, called the Efficient Survival Multifactor Dimensionality Reduction (ES-MDR) method, which used Martingale Residuals as the outcome parameter to estimate survival outcomes, and implemented the Quantitative Multifactor Dimensionality Reduction method to identify significant interactions associated with age of …

Genome-Wide Dna Methylation Profiling In Human Breast Tissue By Illumina Truseq Methyl Capture Epic Sequencing And Infinium Methylationepic Beadchip Microarray, Nan Lin, Jinpeng Liu, James Castle, Jun Wan, Aditi Shendre, Yunlong Liu, Chi Wang, Chunyan He

Markey Cancer Center Faculty Publications

A newly-developed platform, the Illumina TruSeq Methyl Capture EPIC library prep (TruSeq EPIC), builds on the content of the Infinium MethylationEPIC Beadchip Microarray (EPIC-array) and leverages the power of next-generation sequencing for targeted bisulphite sequencing. We empirically examined the performance of TruSeq EPIC and EPIC-array in assessing genome-wide DNA methylation in breast tissue samples. TruSeq EPIC provided data with a much higher density in the regions when compared to EPIC-array (~2.74 million CpGs with at least 10X coverage vs ~752 K CpGs, respectively). Approximately 398 K CpGs were common and measured across the two platforms in every sample. Overall, there …

The Srg Rat, A Sprague-Dawley Rag2/Il2rg Double-Knockout Validated For Human Tumor Oncology Studies, Fallon K. Noto, Jaya Sangodkar, Bisoye Towobola Adedeji, Sam Moody, Christopher B. Mcclain, Ming Tong, Eric Ostertag, Jack Crawford, Xiaohua Gao, Lauren Hurst, Caitlin M. O'Connor, Erika N. Hanson, Sudeh Izadmehr, Rita Tohmé, Jyothsna Narla, Kristin Lesueur, Kajari Bhattacharya, Amit Rupani, Marwan K. Tayeh, Jeffrey W. Innis, Matthew D. Galsky, B. Mark Evers, Analisa Difeo, Goutham Narla, Tseten Y. Jamling

Markey Cancer Center Faculty Publications

We have created the immunodeficient SRG rat, a Sprague-Dawley Rag2/Il2rg double knockout that lacks mature B cells, T cells, and circulating NK cells. This model has been tested and validated for use in oncology (SRG OncoRat®). The SRG rat demonstrates efficient tumor take rates and growth kinetics with different human cancer cell lines and PDXs. Although multiple immunodeficient rodent strains are available, some important human cancer cell lines exhibit poor tumor growth and high variability in those models. The VCaP prostate cancer model is one such cell line that engrafts unreliably and grows irregularly in …

Upregulation Of Cpt1a Is Essential For The Tumor-Promoting Effect Of Adipocytes In Colon Cancer, Xiaopeng Xiong, Yang-An Wen, Rachelle Fairchild, Yekaterina Y. Zaytseva, Heidi L. Weiss, B. Mark Evers, Tianyan Gao

Markey Cancer Center Faculty Publications

Colon tumors grow in an adipose tissue-enriched microenvironment. Locally advanced colon cancers often invade into surrounding adipose tissue with a direct contact with adipocytes. We have previously shown that adipocytes promote tumor growth by modulating cellular metabolism. Here we demonstrate that carnitine palmitoyltransferase I (CPT1A), a key enzyme controlling fatty acid oxidation (FAO), was upregulated in colon cancer cells upon exposure to adipocytes or fatty acids. In addition, CPT1A expression was increased in invasive tumor cells within the adipose tissue compared to tumors without direct contact with adipocytes. Silencing CPT1A abolished the protective effect provided by fatty acids against nutrient …

Egfr Testing And Erlotinib Use In Non-Small Cell Lung Cancer Patients In Kentucky, Kara L. Larson, Bin Huang, Quan Chen, Thomas C. Tucker, Marissa Schuh, Susanne M. Arnold, Jill M. Kolesar

Markey Cancer Center Faculty Publications

This study determined the frequency and factors associated with EGFR testing rates and erlotinib treatment as well as associated survival outcomes in patients with non small cell lung cancer in Kentucky. Data from the Kentucky Cancer Registry (KCR) linked with health claims from Medicaid, Medicare and private insurance groups were evaluated. EGFR testing and erlotinib prescribing were identified using ICD-9 procedure codes and national drug codes in claims, respectively. Logistic regression analysis was performed to determine factors associated with EGFR testing and erlotinib prescribing. Cox-regression analysis was performed to determine factors associated with survival. EGFR mutation testing rates rose from …

Deep Learning Vs. Atlas-Based Models For Fast Auto-Segmentation Of The Masticatory Muscles On Head And Neck Ct Images, Wen Chen, Yimin Li, Brandon A. Dyer, Xue Feng, Shyam Rao, Stanley H. Benedict, Quan Chen, Yi Rong

Markey Cancer Center Faculty Publications

BACKGROUND: Impaired function of masticatory muscles will lead to trismus. Routine delineation of these muscles during planning may improve dose tracking and facilitate dose reduction resulting in decreased radiation-related trismus. This study aimed to compare a deep learning model with a commercial atlas-based model for fast auto-segmentation of the masticatory muscles on head and neck computed tomography (CT) images.

MATERIAL AND METHODS: Paired masseter (M), temporalis (T), medial and lateral pterygoid (MP, LP) muscles were manually segmented on 56 CT images. CT images were randomly divided into training (n = 27) and validation (n = 29) cohorts. Two …

Spermine Synthase And Myc Cooperate To Maintain Colorectal Cancer Cell Survival By Repressing Bim Expression, Yubin Guo, Qing Ye, Pan Deng, Yanan Cao, Daheng He, Zhaohe Zhou, Chi Wang, Yekaterina Y. Zaytseva, Charles E. Schwartz, Eun Young Lee, B. Mark Evers, Andrew J. Morris, Side Liu, Qing-Bai She

Markey Cancer Center Faculty Publications

Dysregulation of polyamine metabolism has been linked to the development of colorectal cancer (CRC), but the underlying mechanism is incompletely characterized. Here, we report that spermine synthase (SMS), a polyamine biosynthetic enzyme, is overexpressed in CRC. Targeted disruption of SMS in CRC cells results in spermidine accumulation, which inhibits FOXO3a acetylation and allows subsequent translocation to the nucleus to transcriptionally induce expression of the proapoptotic protein Bim. However, this induction is blunted by MYC-driven expression of miR-19a and miR-19b that repress Bim production. Pharmacological or genetic inhibition of MYC activity in SMS-depleted CRC cells dramatically induces Bim expression and apoptosis …

Hsp47 Promotes Cancer Metastasis By Enhancing Collagen-Dependent Cancer Cell-Platelet Interaction, Gaofeng Xiong, Jie Chen, Guoying Zhang, Shike Wang, Kunito Kawasaki, Jieqing Zhu, Yan Zhang, Kazuhiro Nagata, Zhenyu Li, Binhua P. Zhou, Ren Xu

Markey Cancer Center Faculty Publications

Increased expression of extracellular matrix (ECM) proteins in circulating tumor cells (CTCs) suggests potential function of cancer cell-produced ECM in initiation of cancer cell colonization. Here, we showed that collagen and heat shock protein 47 (Hsp47), a chaperone facilitating collagen secretion and deposition, were highly expressed during the epithelial-mesenchymal transition (EMT) and in CTCs. Hsp47 expression induced mesenchymal phenotypes in mammary epithelial cells (MECs), enhanced platelet recruitment, and promoted lung retention and colonization of cancer cells. Platelet depletion in vivo abolished Hsp47-induced cancer cell retention in the lung, suggesting that Hsp47 promotes cancer cell colonization by enhancing cancer cell–platelet interaction. …

A Brief Educational Intervention Enhances Basic Cancer Literacy Among Kentucky Middle And High School Students, Lauren Hudson, Kerrigan M. Samons, Haley E. Dicken, Chris Prichard, L. Todd Weiss, Jean Edward, Robin C. Vanderpool, Nathan L. Vanderford

Markey Cancer Center Faculty Publications

Kentucky experiences the highest overall cancer incidence and mortality rates in the USA with the greatest burden in the eastern, Appalachian region of the state. Cancer disparities in Kentucky are driven in part by poor health behaviors, poverty, lack of health care access, low education levels, and low health literacy. Individuals with inadequate health literacy are less likely to participate in preventive measures such as obtaining screenings and making healthy lifestyle choices, thus increasing their chances of developing and dying from cancer. By increasing cancer literacy among youth and adults, it may be possible to decrease cancer disparities across Kentucky. …

Immune-Mediated Genetic Pathways Resulting In Pulmonary Function Impairment Increase Lung Cancer Susceptibility, Linda Kachuri, Mattias Johansson, Sara R. Rashkin, Rebecca E. Graff, Yohan Bossé, Venkata Manem, Neil E. Caporaso, Maria Teresa Landi, David C. Christiani, Paolo Vineis, Geoffrey Liu, Ghislaine Scelo, David Zaridze, Sanjay S Shete, Demetrius Albanes, Melinda C. Aldrich, Adonina Tardón, Gad Rennert, Chu Chen, Gary E. Goodman, Jennifer A. Doherty, Heike Bickeböller, John K. Field, Michael P Davies, M. Dawn Teare, Lambertus A. Kiemeney, Stig E. Bojesen, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Loïc Le Marchand, Iona Cheng, Matthew B. Schabath, Eric J. Duell, Angeline S. Andrew, Jonas Manjer, Philip Lazarus, Susanne M. Arnold, James D. Mckay, Nima C. Emami, Matthew T. Warkentin, Yonathan Brhane, Ma'en Obeidat, Richard M. Martin, Caroline Relton, George Davey Smith, Philip C. Haycock, Christopher I. Amos, Paul Brennan, John S. Witte, Rayjean J. Hung

Markey Cancer Center Faculty Publications

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV₁: r_g = 0.098, p = 2.3 × 10^-8) and the ratio of FEV₁ to forced vital capacity (FEV₁/FVC: r_g = 0.137, p = 2.0 × 10^-12). Mendelian randomization analyses demonstrate that …

Multiple Sclerosis Outcomes After Cancer Immunotherapy, Catherine R. Garcia, Rani Jayswal, Val R. Adams, Lowell B. Anthony, John L. Villano

Markey Cancer Center Faculty Publications

INTRODUCTION: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes.

METHODS: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution.

RESULTS: We identified 14 cases of MS …

N-Glycosylation-Defective Splice Variants Of Neuropilin-1 Promote Metastasis By Activating Endosomal Signals, Xiuping Huang, Qing Ye, Min Chen, Aimin Li, Wenting Mi, Yuxin Fang, Yekaterina Y. Zaytseva, Kathleen L. O'Connor, Craig W. Vander Kooi, Side Liu, Qing-Bai She

Markey Cancer Center Faculty Publications

Neuropilin-1 (NRP1) is an essential transmembrane receptor with a variety of cellular functions. Here, we identify two human NRP1 splice variants resulting from the skipping of exon 4 and 5, respectively, in colorectal cancer (CRC). Both NRP1 variants exhibit increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes. This increased endocytic trafficking of the two NRP1 variants, upon HGF stimulation, is due to loss of N-glycosylation at the Asn150 or Asn261 site, respectively. Moreover, these NRP1 variants enhance interactions with the Met and β1-integrin receptors, resulting in Met/β1-integrin co-internalization and co-accumulation on endosomes. This provides persistent …

Testosterone Levels In Men With Chronic Migraine, Lisa B. E. Shields, Tad Seifert, Brent J. Shelton, Brian M. Plato

Markey Cancer Center Faculty Publications

Chronic migraine is a frequent and debilitating condition affecting 14% of the general population. This prospective observational pilot study investigated whether men with chronic migraine have lower than expected total serum testosterone levels. We identified 14 men ages 26-51 at our Institution who fulfilled the ICHD-3b criteria for chronic migraine and obtained serum total testosterone levels. The mean total testosterone level in our 14 patients was 322 ng/dL (range: 120-542 ng/dL) which is in the lower 5% of the reference range for our laboratory (300-1080 ng/dL). Men with chronic migraine had lower total testosterone levels compared to published agematched normative …

A Novel Function Of Membrane-Associated Collagen In Cancer Metastasis, Hui Zhang, Ren Xu

Markey Cancer Center Faculty Publications

No abstract provided.

Kinase Suppressor Of Ras 1 And Exo70 Promote Fatty Acid-Stimulated Neurotensin Secretion Through Erk1/2 Signaling, Stephanie Rock, Xian Li, Jun Song, Courtney M. Townsend, Heidi L. Weiss, Piotr G. Rychahou, Tianyan Gao, Jing Li, B. Mark Evers

Markey Cancer Center Faculty Publications

Neurotensin is a peptide hormone released from enteroendocrine cells in the small intestine in response to fat ingestion. Although the mechanisms regulating neurotensin secretion are still incompletely understood, our recent findings implicate a role for extracellular signal–regulated kinase 1 and 2 as positive regulators of free fatty acid-stimulated neurotensin secretion. Previous studies have shown that kinase suppressor of Ras 1 acts as a molecular scaffold of the Raf/MEK/extracellular signal–regulated kinase 1 and 2 kinase cascade and regulates intensity and duration of extracellular signal–regulated kinase 1 and 2 signaling. Here, we demonstrate that inhibition of kinase suppressor of Ras 1 attenuates …

Induction Of Ampk Activation By N,N'-Diarylurea Fnd-4b Decreases Growth And Increases Apoptosis In Triple Negative And Estrogen-Receptor Positive Breast Cancers, Jeremy Johnson, Piotr G. Rychahou, Vitaliy M. Sviripa, Heidi L. Weiss, Chunming Liu, David S. Watt, B. Mark Evers

Markey Cancer Center Faculty Publications

Purpose

Triple negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer. AMP-activated protein kinase (AMPK) is a major energy regulator that suppresses tumor growth, and 1-(3-chloro-4-((trifluoromethyl)thio)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea (FND-4b) is a novel AMPK activator that inhibits growth and induces apoptosis in colon cancer. The purpose of this project was to test the effects of FND-4b on AMPK activation, proliferation, and apoptosis in breast cancer with a particular emphasis on TNBC.

Materials and methods

(i) Estrogen-receptor positive breast cancer (ER+BC; MCF-7, and T-47D), TNBC (MDA-MB-231 and HCC-1806), and breast cancer stem cells were treated with FND-4b for 24h. …

Genetic Interaction Analysis Among Oncogenesis-Related Genes Revealed Novel Genes And Networks In Lung Cancer Development, Yafang Li, Xiangjun Xiao, Yohan Bossé, Olga Gorlova, Ivan Gorlov, Younghun Han, Jinyoung Byun, Natasha Leighl, Jakob S. Johansen, Matt Barnett, Chu Chen, Gary Goodman, Angela Cox, Fiona Taylor, Penella Woll, H. Erich Wichmann, Judith Manz, Thomas Muley, Angela Risch, Albert Rosenberger, Jiali Han, Katherine Siminovitch, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria

Markey Cancer Center Faculty Publications

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterationsand tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified …

Shared Heritability And Functional Enrichment Across Six Solid Cancers, Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez

Markey Cancer Center Faculty Publications

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r_g = 0.57, p = 4.6 × 10⁻⁸), breast and ovarian cancer (r_g = 0.24, p = 7 × 10^{−5 …}

P4ha1 Is A New Regulator Of The Hif-1 Pathway In Breast Cancer, Ren Xu

Markey Cancer Center Faculty Publications

Hypoxia-Inducible Factor (HIF)-1 is a transcription factor that plays the key role in response to low oxygen concentrations, or hypoxia. Activation of the HIF-1 pathway is not only crucial for normal tissue development and function, but also involved in disease progression, such as cancer. Cancer cells proliferate rapidly in solid tumors, and thus, solid tumors consume much more oxygen and nutrients than normal tissue and generate oxygen tension. It is well established that oxygen tension in solid tumor tissue induces the aberrant activation of the HIF-1 pathway, and subsequently promotes angiogenesis and tumor progression. Breast cancer is a heterogeneous disease …

Myeloablative Vs Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation For Chronic Myeloid Leukemia, Saurabh Chhabra, Kwang Woo Ahn, Zhen-Huan Hu, Sandeep Jain, Amer Assal, Jan Cerny, Edward A. Copelan, Andrew Daly, Zachariah Defilipp, Shahinaz M Gadalla, Robert Peter Gale, Siddhartha Ganguly, Betty K. Hamilton, Gerhard C. Hildebrandt, Jack W. Hsu, Yoshihiro Inamoto, Abraham S. Kanate, H. Jean Khoury, Hillard M. Lazarus, Mark R. Litzow, Sunita Nathan, Richard F. Olsson, Attaphol Pawarode, Olle Ringden, Jacob M. Rowe, Ayman Saad, Bipin N. Savani, Harry C. Schouten, Sachiko Seo, Nirav N. Shah

Markey Cancer Center Faculty Publications

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients …

Collagen Prolyl 4-Hydroxylase 1 Is Essential For Hif-1Α Stabilization And Tnbc Chemoresistance, Gaofeng Xiong, Rachel L. Stewart, Jie Chen, Tianyan Gao, Timothy L. Scott, Luis M. Samayoa, Kathleen L. O'Connor, Andrew N. Lane, Ren Xu

Markey Cancer Center Faculty Publications

Collagen prolyl 4-hydroxylase (P4H) expression and collagen hydroxylation in cancer cells are necessary for breast cancer progression. Here, we show that P4H alpha 1 subunit (P4HA1) protein expression is induced in triple-negative breast cancer (TNBC) and HER2 positive breast cancer. By modulating alpha ketoglutarate (α-KG) and succinate levels P4HA1 expression reduces proline hydroxylation on hypoxia-inducible factor (HIF) 1α, enhancing its stability in cancer cells. Activation of the P4HA/HIF-1 axis enhances cancer cell stemness, accompanied by decreased oxidative phosphorylation and reactive oxygen species (ROS) levels. Inhibition of P4HA1 sensitizes TNBC to the chemotherapeutic agent docetaxel and doxorubicin in xenografts and patient-derived …

Membrane Associated Collagen Xiii Promotes Cancer Metastasis And Enhances Anoikis Resistance, Hui Zhang, Tricia Fredericks, Gaofeng Xiong, Yifei Qi, Piotr G. Rychahou, Jia-Da Li, Taina Pihlajaniemi, Wei Xu, Ren Xu

Markey Cancer Center Faculty Publications

Background: Increased collagen expression and deposition are associated with cancer progression and poor prognosis in breast cancer patients. However, function and regulation of membrane-associated collagen in breast cancer have not been determined. Collagen XIII is a type II transmembrane protein within the collagen superfamily. Experiments in tissue culture and knockout mouse models show that collagen XIII is involved in cell adhesion and differentiation of certain cell types. In the present study, we determined roles of collagen XIII in breast cancer progression and metastasis.

Methods: We analyzed the association of collagen XIII expression with breast cancer development and metastasis using published …

Fine Mapping Of Mhc Region In Lung Cancer Highlights Independent Susceptibility Loci By Ethnicity, Aida Ferreiro-Iglesias, Corina Lesseur, James Mckay, Rayjean J. Hung, Younghun Han, Xuchen Zong, David Christiani, Mattias Johansson, Xiangjun Xiao, Yafang Li, David C. Qian, Xuemei Ji, Geoffrey Liu, Neil Caporaso, Ghislaine Scelo, David Zaridze, Anush Mukeriya, Milica Kontic, Simona Ognjanovic, Jolanta Lissowska, Małgorzata Szołkowska, Beata Swiatkowska, Vladimir Janout, Ivana Holcatova, Ciprian Bolca, Milan Savic, Miodrag Ognjanovic, Stig Egil Bojesen, Xifeng Wu, Demetrios Albanes, Susanne M. Arnold

Markey Cancer Center Faculty Publications

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In …

Comprehensive Evaluation Of Treatment And Outcomes Of Low-Grade Diffuse Gliomas, Catherine R. Garcia, Stacey A. Slone, Thomas A. Pittman, William H. St. Clair, Donita D. Lightner, John L. Villano

Markey Cancer Center Faculty Publications

Background

Low-grade gliomas affect younger adults and carry a favorable prognosis. They include a variety of biological features affecting clinical behavior and treatment. Having no guidelines on treatment established, we aim to describe clinical and treatment patterns of low-grade gliomas across the largest cancer database in the United States.

Methods

We analyzed the National Cancer Database from 2004 to 2015, for adult patients with a diagnosis of World Health Organization grade II diffuse glioma.

Results

We analyzed 13,621 cases with median age of 41 years. Over 56% were male, 88.4% were white, 6.1% were black, and 7.6% Hispanic. The most …