Medical Genetics Commons^™

Risk Prediction Of Pancreatic Cancer In Patients With Recent-Onset Hyperglycemia: A Machine-Learning Approach, Wansu Chen, Rebecca K Butler, Eva Lustigova, Suresh T Chari, Anirban Maitra, Jo A Rinaudo, Bechien U Wu

Faculty, Staff and Student Publications

Background: New-onset diabetes (NOD) has been suggested as an early indicator of pancreatic cancer. However, the definition of NOD by the American Diabetes Association requires 2 simultaneous or consecutive elevated glycemic measures. We aimed to apply a machine-learning approach using electronic health records to predict the risk in patients with recent-onset hyperglycemia.

Materials and methods: In this retrospective cohort study, health plan enrollees 50 to 84 years of age who had an elevated (6.5%+) glycated hemoglobin (HbA1c) tested in January 2010 to September 2018 with recent-onset hyperglycemia were identified. A total of 102 potential predictors were extracted. Ten imputation datasets …

Radiation Therapy Can Be Safely Incorporated Into Pretransplantation Treatment Regimens For Patients With Multiple Myeloma, Ethan P Damron, Muzaffar H Qazilbash, Penny Q Fang, Susan Y Wu, Bouthaina S Dabaja, Gabriela Rondon, Chitra Hosing, Richard E Champlin, Qaiser Bashir, Elizabeth J Shpall, Mark K Knafl, Hans C Lee, Elisabet E Manasanch, Krina Patel, Sheeba K Thomas, Robert Z Orlowski, Donna M Weber, Chelsea C Pinnix, Jillian R Gunther

Faculty, Staff and Student Publications

Primary treatment of multiple myeloma (MM) often involves systemic induction therapy (SIT) followed by autologous stem cell transplantation (ASCT). Radiation therapy (RT) is sometimes used for palliation; however, many practitioners avoid RT out of concern that future peripheral blood progenitor cell (PBPC) collection required for ASCT may be compromised. In this study, we retrospectively examined the possible effect of RT on PBPC collection. We reviewed the charts of 732 patients with MM treated with RT at our institution from 1999 to 2017, including patients who received RT prior to PBPC collection for planned ASCT. RT plans (both MM and non-MM …

Efficacy Of Cabozantinib In Metastatic Mit Family Translocation Renal Cell Carcinomas, Jonathan Thouvenin, Omar Alhalabi, Maria Carlo, Lucia Carril-Ajuria, Laure Hirsch, Nieves Martinez-Chanza, Sylvie Négrier, Luca Campedel, Dylan Martini, Delphine Borchiellini, Jad Chahoud, Massimo Lodi, Philippe Barthélémy, Elshad Hasanov, Andrew W Hahn, Thierry Gil, Srinivas R Viswanathan, Ziad Bakouny, Pavlos Msaouel, Mehmet Asim Bilen, Toni K Choueiri, Laurence Albiges, Nizar M Tannir, Gabriel G Malouf

Faculty, Staff and Student Publications

Background: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear.

Methods: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS).

Results: Fifty-two patients with metastatic TRCC treated in …

Lenalidomide-Based Maintenance After Autologous Hematopoietic Stem Cell Transplantation For Patients With High-Risk Multiple Myeloma, Oren Pasvolsky, Denái R Milton, Mikael Rauf, Mark R Tanner, Qaiser Bashir, Samer Srour, Guilin Tang, Neeraj Saini, Jeremy Ramdial, Adeel Masood, Yago Nieto, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Maintenance therapy with single-agent lenalidomide (Len) after autologous hematopoietic stem cell transplantation (autoHCT) for multiple myeloma (MM) is associated with improved progression-free survival (PFS). However, MM patients with high-risk chromosomal abnormalities (HRMMs) may need a more intense regimen. We hypothesized that adding another antimyeloma drug to Len maintenance would lead to improved outcomes. We conducted this retrospective single-center chart review analysis of adult HRMM patients who underwent autoHCT between 2008 and 2018, followed by Len-based maintenance therapy. High-risk cytogenetics were defined as del(17p), t(4;14), t(14;16), 1q21 gain or amplification by fluorescence in situ hybridization. We divided patients into those who …

Repeatability And Reproducibility Assessment Of The Apparent Diffusion Coefficient In The Prostate: A Trial Of The Ecog-Acrin Research Group (Acrin 6701), Michael A Boss, Bradley S Snyder, Eunhee Kim, Dena Flamini, Sarah Englander, Karthik M Sundaram, Naveen Gumpeni, Suzanne L Palmer, Haesun Choi, Adam T Froemming, Thorsten Persigehl, Matthew S Davenport, Dariya Malyarenko, Thomas L Chenevert, Mark A Rosen

Faculty, Staff and Student Publications

Background: Uncertainty regarding the reproducibility of the apparent diffusion coefficient (ADC) hampers the use of quantitative diffusion-weighted imaging (DWI) in evaluation of the prostate with magnetic resonance imaging MRI. The quantitative imaging biomarkers alliance (QIBA) profile for quantitative DWI claims a within-subject coefficient of variation (wCV) for prostate lesion ADC of 0.17. Improved understanding of ADC reproducibility would aid the use of quantitative diffusion in prostate MRI evaluation.

Purpose: Evaluation of the repeatability (same-day) and reproducibility (multi-day) of whole-prostate and focal-lesion ADC assessment in a multi-site setting.

Study type: Prospective multi-institutional.

Subjects: Twenty-nine males, ages 53 to 80 (median 63) …

Phase 2 Of Extracellular Rna Communication Consortium Charts Next-Generation Approaches For Extracellular Rna Research, Bogdan Mateescu, Jennifer C Jones, Roger P Alexander, Eric Alsop, Ji Yeong An, Mohammad Asghari, Alex Boomgarden, Laura Bouchareychas, Alfonso Cayota, Hsueh-Chia Chang, Al Charest, Daniel T Chiu, Robert J Coffey, Saumya Das, Peter De Hoff, Andrew Demello, Crislyn D'Souza-Schorey, David Elashoff, Kiarash R Eliato, Jeffrey L Franklin, David J Galas, Mark B Gerstein, Ionita H Ghiran, David B Go, Stephen Gould, Tristan R Grogan, James N Higginbotham, Florian Hladik, Tony Jun Huang, Xiaoye Huo, Elizabeth Hutchins, Dennis K Jeppesen, Tijana Jovanovic-Talisman, Betty Y S Kim, Sung Kim, Kyoung-Mee Kim, Yong Kim, Robert R Kitchen, Vaughan Knouse, Emily L Laplante, Carlito B Lebrilla, L James Lee, Kathleen M Lennon, Guoping Li, Feng Li, Tieyi Li, Tao Liu, Zirui Liu, Adam L Maddox, Kyle Mccarthy, Bessie Meechoovet, Nalin Maniya, Yingchao Meng, Aleksandar Milosavljevic, Byoung-Hoon Min, Amber Morey, Martin Ng, John Nolan, Getulio P De Oliveira Junior, Michael E Paulaitis, Tuan Anh Phu, Robert L Raffai, Eduardo Reátegui, Matthew E Roth, David A Routenberg, Joel Rozowsky, Joseph Rufo, Satyajyoti Senapati, Sigal Shachar, Himani Sharma, Anil K Sood, Stavros Stavrakis, Alessandra Stürchler, Muneesh Tewari, Juan P Tosar, Alexander K Tucker-Schwartz, Andrey Turchinovich, Nedyalka Valkov, Kendall Van Keuren-Jensen, Kasey C Vickers, Lucia Vojtech, Wyatt N Vreeland, Ceming Wang, Kai Wang, Zeyu Wang, Joshua A Welsh, Kenneth W Witwer, David T W Wong, Jianping Xia, Ya-Hong Xie, Kaichun Yang, Mikołaj P Zaborowski, Chenguang Zhang, Qin Zhang, Angela M Zivkovic, Louise C Laurent

Faculty, Staff and Student Publications

The extracellular RNA communication consortium (ERCC) is an NIH-funded program aiming to promote the development of new technologies, resources, and knowledge about exRNAs and their carriers. After Phase 1 (2013-2018), Phase 2 of the program (ERCC2, 2019-2023) aims to fill critical gaps in knowledge and technology to enable rigorous and reproducible methods for separation and characterization of both bulk populations of exRNA carriers and single EVs. ERCC2 investigators are also developing new bioinformatic pipelines to promote data integration through the exRNA atlas database. ERCC2 has established several Working Groups (Resource Sharing, Reagent Development, Data Analysis and Coordination, Technology Development, nomenclature, …

Microbiome Dynamics During Chemoradiation Therapy For Anal Cancer, Daniel Lin, Molly B El Alam, Joseph Abi Jaoude, Ramez Kouzy, Jae L Phan, Jacob H Elnaggar, Brianna Resendiz, Andrea Y Delgado Medrano, Erica J Lynn, Nicholas D Nguyen, Sonal S Noticewala, Geena G Mathew, Emma B Holliday, Bruce D Minsky, Prajnan Das, Van K Morris, Cathy Eng, Melissa P Mezzari, Joseph F Petrosino, Nadim J Ajami, Ann H Klopp, Cullen M Taniguchi, Lauren E Colbert

Faculty, Staff and Student Publications

Purpose: Patients with localized squamous cell carcinoma of the anus (SCCA) who experience treatment toxicity or recurrences have few therapeutic options. Investigation into the microbiome's influence on treatment toxicity and its potential use as a predictive biomarker could improve these patients' outcomes. Our study presents the first longitudinal characterization of the SCCA tumor microbiome and its associations with treatment-related toxicities.

Methods and materials: This prospective cohort study included patients with nonmetastatic SCCA receiving standard-of-care chemoradiation therapy. Anorectal swabs of the tumor site were collected before, during, and after treatment. Patient-reported quality-of-life metrics were collected at similar time points. 16S rRNA …

Phase Ii Study Of Durvalumab (Anti-Pd-L1) And Trametinib (Meki) In Microsatellite Stable (Mss) Metastatic Colorectal Cancer (Mcrc), Benny Johnson, Cara L Haymaker, Edwin R Parra, Luisa Maren Solis Soto, Xuemei Wang, Jane V Thomas, Arvind Dasari, Van K Morris, Kanwal Raghav, Eduardo Vilar, Bryan K Kee, Cathy Eng, Christine M Parseghian, Robert A Wolff, Younghee Lee, Daniele Lorenzini, Caddie Laberiano-Fernandez, Anuj Verma, Wenhua Lang, Ignacio I Wistuba, Andrew Futreal, Scott Kopetz, Michael J Overman

Faculty, Staff and Student Publications

Background: Monotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells.

Methods: Open-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, …

Genetic Risk, Midlife Life's Simple 7, And Incident Dementia In The Atherosclerosis Risk In Communities Study, Adrienne Tin, Jan Bressler, Jeannette Simino, Kevin J Sullivan, Hao Mei, B Gwen Windham, Michael Griswold, Rebecca F Gottesman, Eric Boerwinkle, Myriam Fornage, Thomas H Mosley

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Higher scores in Life's Simple 7 (LS7), a metric for cardiovascular and brain health, have been associated with lower risk of dementia. It is uncertain whether this association holds among those with high genetic risk of dementia. Our objective is to evaluate the extent that LS7 may offset dementia risk across the range of genetic risk.

METHODS: Participants in the Atherosclerosis Risk in Communities (ARIC) Study were followed from 1987-1989 to 2019. We derived midlife LS7 scores and generated genetic risk scores (GRS) using genome-wide summary statistics of Alzheimer disease, which have been used to study the …

Urgent Cytoreduction For Newly Diagnosed Acute Myeloid Leukemia Patients Allows Acquisition Of Pretreatment Genomic Data And Enrollment On Investigational Clinical Trials, Kunhwa Kim, Marina Konopleva, Courtney D Dinardo, Gautam Borthakur, Sanam Loghavi, Guilin Tang, Naval Daver, Naveen Pemmaraju, Elias Jabbour, Caitlin R Rausch, Musa Yilmaz, Koji Sasaki, Nicholas J Short, Nitin Jain, Mark Brandt, Sherry Pierce, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Newly diagnosed acute myeloid leukemia is often deemed a medical emergency, requiring urgent treatment. This is in contradiction with the need for accurate cytogenetic and molecular data, which is not immediately available, to select optimal therapy. We hypothesized that cytoreduction with hydroxyurea or cytarabine would enable urgent disease control and provide a bridge to clinical trial enrollment. We analyzed three prospective frontline clinical trials that allowed the use of cytoreduction before treatment initiation. Among 274 patients with a median age of 62 (range, 18-89), there was no significant difference in short- and long-term outcome and safety among patients who did …

Cardiovascular Events In Patients Treated With Chimeric Antigen Receptor T-Cell Therapy For Aggressive B-Cell Lymphoma, Raphael E Steiner, Jose Banchs, Efstratios Koutroumpakis, Melody Becnel, Cristina Gutierrez, Paolo Strati, Chelsea C Pinnix, Lei Feng, Gabriela Rondon, Catherine Claussen, Nicolas Palaskas, Kaveh Karimzad, Sairah Ahmed, Sattva S Neelapu, Elizabeth Shpall, Michael Wang, Francisco Vega, Jason Westin, Loretta J Nastoupil, Anita Deswal

Faculty, Staff and Student Publications

Standard of care (SOC) chimeric antigen receptor (CAR) T-cell therapies such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are associated with multisystem toxicities. There is limited information available about cardiovascular (CV) events associated with SOC axi-cel or tisa-cel. Patients with CV comorbidities, organ dysfunction, or lower performance status were often excluded in the clinical trials leading to their Food and Drug Adminsitration approval. An improved understanding of CV toxicities in the real-world setting will better inform therapy selection and management of patients receiving these cellular therapies. Here, we retrospectively reviewed the characteristics and outcomes of adult patients with relapsed/refractory large …

Real-World Use Of Palbociclib Monotherapy In Retroperitoneal Liposarcomas At A Large Volume Sarcoma Center, Elise F Nassif, Brandon Cope, Raymond Traweek, Russell G Witt, Derek J Erstad, Christopher P Scally, Prapassorn Thirasastr, Maria Alejandra Zarzour, Joseph Ludwig, Robert Benjamin, Andrew J Bishop, B Ashleigh Guadagnolo, Davis Ingram, Khalida Wani, Wei-Lien Wang, Alexander J Lazar, Keila E Torres, Kelly K Hunt, Barry W Feig, Christina L Roland, Neeta Somaiah, Emily Z Keung

Faculty, Staff and Student Publications

Palbociclib has been evaluated in early phase trials for well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) patients, with reported median progression-free survival (PFS) of 18 weeks. Here, we report on real-world use and surgical outcomes associated with palbociclib treatment. We retrospectively reviewed 61 consecutive patients with retroperitoneal WDLPS (n = 14) or DDLPS (n = 47) treated with palbociclib monotherapy between 1 March 2016 and 28 February 2021 at The University of Texas MD Anderson Cancer Center. At palbociclib initiation, median age was 64 (interquartile range [IQR] 56-72). In WDLPS and DDLPS cohorts, the median number of prior systemic treatments …

Success And Outcomes Following A Second Salvage Attempt For Free Flap Compromise In Patients Undergoing Head And Neck Reconstruction, Allison A Slijepcevic, Gavin Young, Justin Shinn, Steven B Cannady, Matthew Hanasono, Matthew Old, Jeewanjot S Grewal, Tamer Ghanem, Yadranko Ducic, Joseph M Curry, Mark K Wax

Faculty, Staff and Student Publications

Importance: Incidence of perioperative free flap compromise is low, with successful salvage in up to 70%. When the flap is compromised a second time, the value of intervening is unknown.

Objective: To assess the outcomes of a second revascularization attempt for compromised free flaps.

Design, setting, and participants: This multicenter retrospective medical record review included patients undergoing head and neck reconstruction with free flaps at 6 US medical centers from January 1, 2000, through December 30, 2020. Patients were 18 years or older with a history of head and neck defects from cancer, osteoradionecrosis, or other wounds. Of 3510 flaps …

Venetoclax Combined With Induction Chemotherapy In Patients With Newly Diagnosed Acute Myeloid Leukaemia: A Post-Hoc, Propensity Score-Matched, Cohort Study, Curtis A Lachowiez, Patrick K Reville, Hagop Kantarjian, Elias Jabbour, Gautam Borthakur, Naval Daver, Sanam Loghavi, Ken Furudate, Lianchun Xiao, Sherry Pierce, Nicholas J Short, Abhishek Maiti, Musa Yilmaz, Koji Sasaki, Koichi Takahashi, Marina Konopleva, Naveen Pemmaraju, Uday Popat, Elizabeth Shpall, Guillermo Garcia-Manero, Farhad Ravandi, Courtney D Dinardo, Tapan M Kadia

Faculty, Staff and Student Publications

Background: Venetoclax combined with intensive chemotherapy has been shown to be safe with promising activity in fit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to compare the activity of venetoclax plus intensive chemotherapy with intensive chemotherapy alone.

Methods: This was a post-hoc propensity score matched analysis of prospective clinical trials (NCT03214562, NCT02115295, and NCT01289457) in patients at The University of Texas MD Anderson Cancer Center, Texas, USA between March 29, 2010, and June 15, 2021. Eligible patients were aged 18 years and older, and had newly diagnosed acute myeloid leukaemia …

Combined Il-2, Agonistic Cd3 And 4–1bb Stimulation Preserve Clonotype Hierarchy In Propagated Non-Small Cell Lung Cancer Tumor-Infiltrating Lymphocytes, Parin Shah, Marie-Andrée Forget, Meredith L Frank, Peixin Jiang, Donastas Sakellariou-Thompson, Lorenzo Federico, Roohussaba Khairullah, Chantal Alexia Neutzler, Ignacio Wistuba, Chi-Wan B Chow, Yan Long, Junya Fujimoto, Shiaw-Yih Lin, Anirban Maitra, Marcelo V Negrao, Kyle Gregory Mitchell, Annikka Weissferdt, Ara A Vaporciyan, Tina Cascone, Jack A Roth, Jianjun Zhang, Boris Sepesi, Don L Gibbons, John V Heymach, Cara L Haymaker, Daniel J Mcgrail, Alexandre Reuben, Chantale Bernatchez

Faculty, Staff and Student Publications

Background: Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) yielded clinical benefit in patients with checkpoint blockade immunotherapy-refractory non-small cell lung cancer (NSCLC) prompting a renewed interest in TIL-ACT. This preclinical study explores the feasibility of producing a NSCLC TIL product with sufficient numbers and enhanced attributes using an improved culture method.

Methods: TIL from resected NSCLC tumors were initially cultured using (1) the traditional method using interleukin (IL)-2 alone in 24-well plates (TIL 1.0) or (2) IL-2 in combination with agonistic antibodies against CD3 and 4-1BB (Urelumab) in a G-Rex flask (TIL 3.0). TIL subsequently underwent a rapid expansion …

Gene-Gene Interaction Of Ahrwith And Within The Wntcascade Affects Susceptibility To Lung Cancer, Albert Rosenberger, Nils Muttray, Rayjean J Hung, David C Christiani, Neil E Caporaso, Geoffrey Liu, Stig E Bojesen, Loic Le Marchand, Demetrios Albanes, Melinda C Aldrich, Adonina Tardon, Guillermo Fernández-Tardón, Gad Rennert, John K Field, Michael P A Davies, Triantafillos Liloglou, Lambertus A Kiemeney, Philip Lazarus, Bernadette Wendel, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Matthew B Schabath, Angeline S Andrew, Eric J Duell, Susanne M Arnold, Gary E Goodman, Chu Chen, Jennifer A Doherty, Fiona Taylor, Angela Cox, Penella J Woll, Angela Risch, Thomas R Muley, Mikael Johansson, Paul Brennan, Maria Teresa Landi, Sanjay S Shete, Christopher I Amos, Heike Bickeböller, Integral-Ilcco Consortium

Faculty, Staff and Student Publications

Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility.

Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent.

Methods: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung …

Clonal Hematopoiesis Mutations In Patients With Lung Cancer Are Associated With Lung Cancer Risk Factors, Wei Hong, Ang Li, Yanhong Liu, Xiangjun Xiao, David C Christiani, Rayjean J Hung, James Mckay, John Field, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

Clonal hematopoiesis (CH) is a phenomenon caused by expansion of white blood cells descended from a single hematopoietic stem cell. While CH can be associated with leukemia and some solid tumors, the relationship between CH and lung cancer remains largely unknown. To help clarify this relationship, we analyzed whole-exome sequencing (WES) data from 1,958 lung cancer cases and controls. Potential CH mutations were identified by a set of hierarchical filtering criteria in different exonic regions, and the associations between the number of CH mutations and clinical traits were investigated. Family history of lung cancer (FHLC) may exert diverse influences on …

Cancer Prevention Behaviors In Workers Of A Referral Cancer Center In Mexico City: A Pilot Study On Early Detection Awareness For Cancer, Nancy Reynoso-Noverón, Shine Chang, Luis Alonso Herrera-Montalvo, Abelardo Meneses-García

Faculty, Staff and Student Publications

Background: Prevention strategies for cancer are necessary. Health workers who often serve as role models bear responsibility for prevention counseling and programs. However, whether their habits and behaviors reflect prevention goals are unknown. We describe the prevalence of cancer risk factors and prevention behaviors in health workers of a referral cancer center in Mexico City.

Methods: Cross-sectional study in which workers of the National Cancer Institute were invited to participate in a prevention program, risk factor survey, and nutrition, psychological, and genetic counseling were included. The likelihood of cancer was calculated based on the presence of risk factors. Factors associated …

Donor Selection For Kir Alloreactivity Is Associated With Superior Survival In Haploidentical Transplant With Ptcy, Jun Zou, Piyanuch Kongtim, Samer A Srour, Uri Greenbaum, Johannes Schetelig, Falk Heidenreich, Henning Baldauf, Brandt Moore, Supawee Saengboon, Yudith Carmazzi, Gabriela Rondon, Qing Ma, Katayoun Rezvani, Elizabeth J Shpall, Richard E Champlin, Stefan O Ciurea, Kai Cao

Faculty, Staff and Student Publications

With the continuous increase in the use of haploidentical donors for transplantation, the selection of donors becomes increasingly important. Haploidentical donors have been selected primarily based on clinical characteristics, while the effects of killer cell immunoglobulin-like receptors (KIRs) on outcomes of haploidentical-hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) remain inconclusive. The present study aimed to thoroughly evaluate the effect of KIRs and binding ligands assessed by various models, in addition to other patient/donor variables, on clinical outcomes in haplo-HSCT. In a cohort of 354 patients undergoing their first haplo-HSCT, we found that a higher Count Functional inhibitory KIR …

Prediction Of Early (4-Week) Mortality In Acute Myeloid Leukemia With Intensive Chemotherapy, Koji Sasaki, Tapan Kadia, Kebede Begna, Courtney D Dinardo, Gautam Borthakur, Nicholas J Short, Nitin Jain, Naval Daver, Elias Jabbour, Guillermo Garcia-Manero, Guillermo Montalban Bravo, Lucia Masarova, Sherry Pierce, Marina Konopleva, Farhad Ravandi, Ayalew Tefferi, Hagop Kantarjian

Faculty, Staff and Student Publications

The progress with intensive chemotherapy and supportive care measures has improved survival in patients with newly diagnosed acute myeloid leukemia (AML). Given the recent development of effective low intensity therapies, an optimal decision on the therapy intensity may improve survival through the avoidance of early mortality. We reviewed the outcome of 3728 patients with newly diagnosed AML who received intensive chemotherapy between August 1980 and May 2020. Intensive chemotherapy was defined as a cumulative cytarabine dose ≥ 700 mg/m2 during induction therapy. We divided the whole cohort into a training and validation group at a 3:1 ratio. The population was …

Epilepsy Risk Prediction Model For Patients With Tuberous Sclerosis Complex, Laura S Farach, Melissa A Richard, Philip J Lupo, Mustafa Sahin, Darcy A Krueger, Joyce Y Wu, Elizabeth M Bebin, Kit Sing Au, Hope Northrup, Tacern Study Group

Faculty, Staff and Student Publications

BACKGROUND: Individuals with tuberous sclerosis complex are at increased risk of epilepsy. Early seizure control improves developmental outcomes, making identifying at-risk patients critically important. Despite several identified risk factors, it remains difficult to predict. The purpose of the study was to evaluate the combined risk prediction of previously identified risk factors for epilepsy in individuals with tuberous sclerosis complex.

METHODS: The study group (n = 333) consisted of individuals with tuberous sclerosis complex who were enrolled in the Tuberous Sclerosis Complex Autism Center of Excellence Research Network and UT TSC Biobank. The outcome was defined as having an epilepsy diagnosis. …

Genetics Of Smoking Behaviors In American Indians, Jeffrey A Henderson, Dedra S Buchwald, Barbara V Howard, Patricia Nez Henderson, Yafang Li, Rachel F Tyndale, Christopher I Amos, Olga Y Gorlova, Collaborative To Improve Native Cancer Outcomes (Cinco), A P50 Center For Population Health And Health Disparities Program Project Sponsored By The National Cancer Institute

Faculty, Staff and Students Publications

BACKGROUND: The smoking behavior of American Indians (AI) differs from that of non-Hispanic whites (NHW). Typically light smokers, cessation interventions in AIs are generally less effective. To develop more effective cessation programs for AIs, clinicians, researchers, and public health workers need a better understanding of the genetic factors involved in their smoking behavior. Our aim was to assess whether SNPs associated with smoking behavior in NHWs are also associated with smoking in AIs.

METHODS: We collected questionnaire data on smoking behaviors and analyzed blood and saliva samples from two Tribal populations with dramatically different cultures and smoking prevalence, one in …

Association Analysis Of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci With 20,871 Lung Cancer Cases And 15,971 Controls, Yuzhuo Wang, Olga Y Gorlova, Ivan P Gorlov, Meng Zhu, Juncheng Dai, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Gary E Goodman, Stig E Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, Heunz-Erich Wichmann, Heike Bickeboller, David C Christiani, Gad Rennert, Susanne M Arnold, Paul Brennan, John K Field, Sanjay Shete, Loïc Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Rayjean J Hung, Angeline S Andrew, Lambertus A Kiemeney, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil E Caporaso, Penella J Woll, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Victoria L Stevens, Hongxia Ma, Guangfu Jin, Zhibin Hu, Christopher I Amos, Hongbing Shen

Faculty, Staff and Students Publications

BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.

METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data …

Rheumatoid Arthritis-Relevant Dna Methylation Changes Identified In Acpa-Positive Asymptomatic Individuals Using Methylome Capture Sequencing., Xiaojian Shao, Marie Hudson, Ines Colmegna, Celia M T Greenwood, Marvin J. Fritzler, Philip Awadalla, T Pastinen, Sasha Bernatsky

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk.

METHODS: With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. …

Dissecting Features Of Epigenetic Variants Underlying Cardiometabolic Risk Using Full-Resolution Epigenome Profiling In Regulatory Elements., Fiona Allum, Åsa K. Hedman, Xiaojian Shao, Warren A. Cheung, Jinchu Vijay, Frédéric Guénard, Tony Kwan, Marie-Michelle Simon, Bing Ge, Cristiano Moura, Elodie Boulier, Lars Rönnblom, Sasha Bernatsky, Mark Lathrop, Mark I. Mccarthy, Panos Deloukas, André Tchernof, T Pastinen, Marie-Claude Vohl, Elin Grundberg

Manuscripts, Articles, Book Chapters and Other Papers

Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up …

Genomic Prediction Of Relapse In Recipients Of Allogeneic Haematopoietic Stem Cell Transplantation., J Ritari, K Hyvärinen, S Koskela, M Itälä-Remes, R Niittyvuopio, A Nihtinen, U Salmenniemi, M Putkonen, L Volin, T Kwan, T Pastinen, J Partanen

Manuscripts, Articles, Book Chapters and Other Papers

Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the …

An Eqtl Landscape Of Kidney Tissue In Human Nephrotic Syndrome., Christopher E. Gillies, Rosemary Putler, Rajasree Menon, Edgar Otto, Kalyn Yasutake, Viji Nair, Paul Hoover, David Lieb, Shuqiang Li, Sean Eddy, Damian Fermin, Michelle T. Mcnulty, Nephrotic Syndrome Study Network (Neptune), Nir Hacohen, Krzysztof Kiryluk, Matthias Kretzler, Xiaoquan Wen, Matthew G. Sampson, Tarak Srivastava

Manuscripts, Articles, Book Chapters and Other Papers

Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTL studies of human kidney. Here, we used whole-genome sequencing (WGS) and microdissected glomerular (GLOM) and tubulointerstitial (TI) transcriptomes from 187 individuals with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures. Using MatrixEQTL, we performed cis-eQTL analysis on GLOM (n = 136) and TI (n = 166). We used the Bayesian "Deterministic Approximation of Posteriors" (DAP) to fine-map …

Novel Hla-Dp Region Susceptibility Loci Associated With Severe Acute Gvhd., Rakesh K. Goyal, S J. Lee, T Wang, M Trucco, M Haagenson, S R. Spellman, M Verneris, R E. Ferrell

Manuscripts, Articles, Book Chapters and Other Papers

Despite HLA allele matching, significant acute GvHD remains a major barrier to successful unrelated donor BMT. We conducted a genome-wide association study (GWAS) to identify recipient and donor genes associated with the risk of acute GvHD. A case-control design (grade III-IV versus no acute GvHD) and pooled GWA approach was used to study European-American recipients with hematological malignancies who received myeloablative conditioning non-T-cell-depleted first transplantation from HLA-A, -B, -C, -DRB1, -DQB1 allele level (10/10) matched unrelated donors. DNA samples were divided into three pools and tested in triplicate using the Affymetrix Genome-wide SNP Array 6.0. We identified three novel susceptibility …

An Integrated Clinico-Metabolomic Model Improves Prediction Of Death In Sepsis., Raymond J. Langley, Ephraim L. Tsalik, Jennifer C. Van Velkinburgh, Seth W. Glickman, Brandon J. Rice, Chunping Wang, Bo Chen, Lawrence Carin, Arturo Suarez, Robert P. Mohney, Debra H. Freeman, Mu Wang, Jinsam You, Jacob Wulff, J Will Thompson, M Arthur Moseley, Stephanie Reisinger, Brian T. Edmonds, Brian Grinnell, David R. Nelson, Darrell L. Dinwiddie, Neil A. Miller, Carol J. Saunders, Sarah Soden, Angela J. Rogers, Lee Gazourian, Laura E. Fredenburgh, Anthony F. Massaro, Rebecca M. Baron, Augustine M K Choi, G Ralph Corey, Geoffrey S. Ginsburg, Charles B. Cairns, Ronny M. Otero, Vance G. Fowler, Emanuel P. Rivers, Christopher W. Woods, Stephen F. Kingsmore

Manuscripts, Articles, Book Chapters and Other Papers

Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would ultimately die differed markedly from those of patients who would survive. The different profiles of proteins and metabolites clustered into the …

Cytoplasmic Localization Of Alteration/Deficiency In Activation 3 (Ada3) Predicts Poor Clinical Outcome In Breast Cancer Patients., Sameer Mirza, Emad A. Rakha, Alaa Alshareeda, Shakur Mohibi, Xiangshan Zhao, Bryan J. Katafiasz, Jun Wang, Channabasavaiah B. Gurumurthy, Aditya Bele, Ian O. Ellis, Andrew R. Green, Hamid Band, Vimla Band

Journal Articles: Genetics, Cell Biology & Anatomy

Transcriptional activation by estrogen receptor (ER) is a key step to breast oncogenesis. Given previous findings that ADA3 is a critical component of HAT complexes that regulate ER function and evidence that overexpression of other ER coactivators such as SRC-3 is associated with clinical outcomes in breast cancer, the current study was designed to assess the potential significance of ADA3 expression/localization in human breast cancer patients. In this study, we analyzed ADA3 expression in breast cancer tissue specimens and assessed the correlation of ADA3 staining with cancer progression and patient outcome. Tissue microarrays prepared from large series of breast cancer …