Genetic Phenomena Commons^™

Impact Of Renal Cell Carcinoma Molecular Subtypes On Immunotherapy And Targeted Therapy Outcomes, Renée Maria Saliby, Chris Labaki, Tejas R Jammihal, Wanling Xie, Maxine Sun, Eddy Saad, Soki Kashima, Katherine Sadak, Talal El Zarif, Deepak Poduval, Robert J Motzer, Thomas Powles, Brian I Rini, Laurence Albiges, Sumanta K Pal, Bradley A Mcgregor, Rana R Mckay, Sabina Signoretti, Eliezer M Van Allen, Sachet A Shukla, Toni K Choueiri, David A Braun

Faculty, Staff and Student Publications

Saliby et al. show that a machine learning approach can accurately classify clear cell renal cell carcinoma (RCC) into distinct molecular subtypes using transcriptomic data. When applied to tumors biospecimens from the JAVELIN Renal 101 (JR101) trial, a benefit is observed with immune checkpoint inhibitor (ICI)-based therapy across all molecular subtypes.

The Crosstalk Between Macrophages And Cancer Cells Potentiates Pancreatic Cancer Cachexia, Mingyang Liu, Yu Ren, Zhijun Zhou, Jingxuan Yang, Xiuhui Shi, Alex X Arreola, Kar-Ming Fung, Chao Xu, Ryan D Nipp, Michael S Bronze, Lei Zheng, Yi-Ping Li, Courtney W Houchen, Yuqing Zhang, Min Li

Faculty, Staff and Student Publications

With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis …

Regulation Of Cerebral Blood Flow Boosts Precise Brain Targeting Of Vinpocetine-Derived Ionizable-Lipidoid Nanoparticles, Xufei Bian, Ling Yang, Dingxi Jiang, Adam J Grippin, Yifan Ma, Linchong Wu, Zhongjie Tang, Kaicheng Tang, Weidong Pan, Shiyan Dong, Betty Y S Kim, Wen Jiang, Zhaogang Yang, Chong Li

Faculty, Staff and Student Publications

Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid …

Inotuzumab Ozogamicin For The Treatment Of Adult Acute Lymphoblastic Leukemia: Past Progress, Current Research And Future Directions, Nicholas J Short, Elias Jabbour, Nitin Jain, Hagop Kantarjian

Faculty, Staff and Student Publications

Inotuzumab ozogamicin (INO) is an anti-CD22 antibody-drug conjugate that was first evaluated in B-cell lymphomas but was subsequently shown to be highly effective in acute lymphoblastic leukemia (ALL). INO improved response rates and survival in a randomized study in adults with relapsed/refractory B-cell ALL, leading to its regulatory approval in the United States in 2017. While the formal approval for INO is as monotherapy in relapsed/refractory ALL, subsequent studies with INO administered in combination with chemotherapy and/or blinatumomab both in the frontline and salvage settings have yielded promising results. In this review, we discuss the clinical development of INO in …

Clinical, Genetic, And Cognitive Correlates Of Seizure Occurrences In Phelan-Mcdermid Syndrome, Tess Levy, Jacob Gluckman, Paige M Siper, Danielle Halpern, Jessica Zweifach, Rajna Filip-Dhima, J Lloyd Holder, M Pilar Trelles, Kristina Johnson, Jonathan A Bernstein, Elizabeth Berry-Kravis, Craig M Powell, Latha Valluripalli Soorya, Audrey Thurm, Joseph D Buxbaum, Mustafa Sahin, Alexander Kolevzon, Siddharth Srivastava

Duncan NRI Faculty and Staff Publications

Background: Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome.

Methods: We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, …

Casi: A Framework For Cross-Timepoint Analysis Of Single-Cell Rna Sequencing Data, Yizhuo Wang, Christopher R Flowers, Michael Wang, Xuelin Huang, Ziyi Li

Faculty, Staff and Student Publications

Single-cell RNA sequencing (scRNA-seq) technology has been widely used to study the differences in gene expression at the single cell level, providing insights into the research of cell development, differentiation, and functional heterogeneity. Various pipelines and workflows of scRNA-seq analysis have been developed but few considered multi-timepoint data specifically. In this study, we develop CASi, a comprehensive framework for analyzing multiple timepoints' scRNA-seq data, which provides users with: (1) cross-timepoint cell annotation, (2) detection of potentially novel cell types emerged over time, (3) visualization of cell population evolution, and (4) identification of temporal differentially expressed genes (tDEGs). Through comprehensive simulation …

Imaging Features Of Primary Intracranial Sarcoma With Dicer1 Mutation: A Multicenter Case Series, Rami W Eldaya, Richard J Fagan, Samir A Dagher, Angshumoy Roy, Sonika Dahyia, Max Wintermark, Thierry A G M Huisman

Faculty, Staff and Student Publications

Primary intracranial sarcoma, DICER1-mutant, is a rare, recently described entity in the fifth edition of the WHO Classification of CNS Tumors. Given the entity's rarity and recent description, imaging data on primary intracranial sarcoma, DICER1-mutant, remains scarce. In this multicenter case series, we present detailed multimodality imaging features of primary intracranial sarcoma, DICER1-mutant, with emphasis on the appearance of the entity on MR imaging. In total, 8 patients were included. In all 8 patients, the lesion demonstrated blood products on T1WI. In 7 patients, susceptibility-weighted imaging was obtained and demonstrated blood products. Primary intracranial sarcoma, DICER1-mutant, …

Response To Lao, Guan, Wang, Et Al, Casey Crump, Pär Stattin, James D Brooks, Jan Sundquist, Alexis C Edwards, Weiva Sieh

Faculty, Staff and Student Publications

No abstract provided.

Correction: Horne Et Al White Matter Correlates Of Domain-Specific Working Memory, Autumn Horne, Junhua Ding, Tatiana T Schnur, Randi C Martin

Faculty, Staff and Student Publications

In the original publication [...].

Exome Sequencing Implicates Ancestry-Related Mendelian Variation At Syne1 In Childhood-Onset Essential Hypertension, Ian Copeland, Edmond Wonkam-Tingang, Monesha Gupta-Malhotra, S Shahrukh Hashmi, Yixing Han, Nancy J Hall, Natasha Lie, Dan Liu, Jun Xu, Jill Rosenfeld, Aparna Haldipur, Zelene Desire, Zeynep H Coban-Akdemir, Daryl A Scott, Qing Li, Hsiao-Tuan Chao, Ana M Zaske, James R Lupski, Dianna M Milewicz, Sanjay Shete, Jennifer E Posey, Neil A Hanchard

Faculty, Staff and Student Publications

Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date. Here, we identify recessive segregation of rare and putatively damaging missense variation in the spectrin domain of spectrin repeat containing nuclear envelope …

Single Extracellular Vesicle Imaging And Computational Analysis Identifies Inherent Architectural Heterogeneity, Kshipra S Kapoor, Seoyun Kong, Hikaru Sugimoto, Wenhua Guo, Vivek Boominathan, Sibani Lisa Biswal, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Evaluating the heterogeneity of extracellular vesicles (EVs) is crucial for unraveling their complex actions and biodistribution. Here, we identify consistent architectural heterogeneity of EVs using cryogenic transmission electron microscopy (cryo-TEM), which has an inherent ability to image biological samples without harsh labeling methods while preserving their native conformation. Imaging EVs isolated using different methodologies from distinct sources, such as cancer cells, normal cells, immortalized cells, and body fluids, we identify a structural atlas of their dominantly consistent shapes. We identify EV architectural attributes by utilizing a segmentation neural network model. In total, 7,576 individual EVs were imaged and quantified by …

Histone Demethylase Kdm5 Regulates Cardiomyocyte Maturation By Promoting Fatty Acid Oxidation, Oxidative Phosphorylation, And Myofibrillar Organization, Manisha Deogharia, Leslye Venegas-Zamora, Akanksha Agrawal, Miusi Shi, Abhinav K Jain, Francisco Altamirano, Priyatansh Gurha

Faculty, Staff and Student Publications

Aims: Human pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) provide a platform to identify and characterize factors that regulate the maturation of CMs. The transition from an immature foetal to an adult CM state entails coordinated regulation of the expression of genes involved in myofibril formation and oxidative phosphorylation (OXPHOS) among others. Lysine demethylase 5 (KDM5) specifically demethylates H3K4me1/2/3 and has emerged as potential regulators of expression of genes involved in cardiac development and mitochondrial function. The purpose of this study is to determine the role of KDM5 in iPSC-CM maturation.

Methods and results: KDM5A, B, and C proteins were mainly expressed …

Data Normalization For Addressing The Challenges In The Analysis Of Single-Cell Transcriptomic Datasets, Raquel Cuevas-Diaz Duran, Haichao Wei, Jiaqian Wu

Faculty, Staff and Student Publications

BACKGROUND: Normalization is a critical step in the analysis of single-cell RNA-sequencing (scRNA-seq) datasets. Its main goal is to make gene counts comparable within and between cells. To do so, normalization methods must account for technical and biological variability. Numerous normalization methods have been developed addressing different sources of dispersion and making specific assumptions about the count data.

MAIN BODY: The selection of a normalization method has a direct impact on downstream analysis, for example differential gene expression and cluster identification. Thus, the objective of this review is to guide the reader in making an informed decision on the most …

Evaluating The Heterogeneity Of Hippocampal Avoidant Whole Brain Radiotherapy Treatment Effect: A Secondary Analysis Of Nrg Cc001, Hua-Ren R Cherng, Kai Sun, Søren Bentzen, Terri S Armstrong, Vinai Gondi, Minesh Mehta

Faculty, Staff and Student Publications

Background: Hippocampal avoidant whole brain radiotherapy (HA-WBRT) is the standard of care for patients needing WBRT for brain metastases. This study, using existing data from NRG Oncology CC001 including baseline tumor characteristics and patient-reported MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) scores, sought to identify subgroups of patients that demonstrate differential neuroprotective treatment response to HA-WBRT.

Methods: An exploratory analysis of NRG CC001, a phase 3 trial in which 518 patients were randomly assigned to WBRT plus memantine or HA-WBRT plus memantine, was performed. Rates of neurocognitive function failure (NCFF) were estimated between subgroups and stratified by arm. Covariate and subgroup …

A Comprehensive Approach To Evaluate Genetic Abnormalities In Multiple Myeloma Using Optical Genome Mapping, Ying S Zou, Melanie Klausner, Jen Ghabrial, Victoria Stinnett, Patty Long, Jaclyn B Murry, Christopher D Gocke, Rena R Xian, Kevin H Toomer, Jing Christine Ye, Robert Z Orlowski, Carol Ann Huff, Syed Abbas Ali, Philip H Imus, Christian B Gocke, Guilin Tang

Faculty, Staff and Student Publications

No abstract provided.

Focal Adhesion Kinase-Yap Signaling Axis Drives Drug-Tolerant Persister Cells And Residual Disease In Lung Cancer, Franziska Haderk, Yu-Ting Chou, Lauren Cech, Celia Fernández-Méndez, Johnny Yu, Ismail M Meraz, D Lucas Kerr, Carlos Gomez, David V Allegakoen, Juan Guan, Khyati N Shah, Kari A Herrington, Oghenekevwe M Gbenedio, Shigeki Nanjo, Mourad Majidi, Whitney Tamaki, Yashar K Pourmoghadam, Julia K Rotow, Caroline E Mccoach, Jonathan W Riess, J Silvio Gutkind, Tracy T Tang, Leonard Post, Bo Huang, Pilar Santisteban, Hani Goodarzi, Sourav Bandyopadhyay, Calvin J Kuo, Jeroen P Roose, Wei Wu, Collin M Blakely, Jack A Roth, Trever G Bivona

Faculty, Staff and Student Publications

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling …

Triggering Receptor Expressed On Myeloid Cells 2 (Trem2) Regulates Phagocytosis In Glioblastoma, Mekenzie M Peshoff, Pravesh Gupta, Shivangi Oberai, Rakesh Trivedi, Hiroshi Katayama, Minghao Dang, Joy Gumin, Divya B Kadri, Jessica K Lin, Nancy K Milam, Mark E Maynard, Brian D Vaillant, Brittany Parker-Kerrigan, Frederick F Lang, Jason T Huse, Antonio Iavarone, Linghua Wang, Karen Clise-Dwyer, Krishna P Bhat

Faculty, Staff and Student Publications

Background: Glioblastomas (GBMs) are central nervous system tumors that resist standard-of-care interventions and even immune checkpoint blockade. Myeloid cells in the tumor microenvironment can contribute to GBM progression; therefore, emerging immunotherapeutic approaches include reprogramming these cells to achieve desirable antitumor activity. Triggering receptor expressed on myeloid cells 2 (TREM2) is a myeloid signaling regulator that has been implicated in a variety of cancers and neurological diseases with contrasting functions, but its role in GBM immunopathology and progression is still under investigation.

Methods: Our reverse translational investigations leveraged single-cell RNA sequencing and cytometry of human gliomas to characterize TREM2 expression across …

Fam86a Methylation Of Eef2 Links Mrna Translation Elongation To Tumorigenesis, Joel William Francis, Simone Hausmann, Sabeen Ikram, Kunlun Yin, Robert Mealey-Farr, Annie Truc Trinh, Julia Thompson, Pawel Karol Mazur, Or Gozani

Faculty, Staff and Student Publications

eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation. FAM86A depletion in LUAD cells causes 80S monosome accumulation and mRNA translation inhibition. FAM86A is overexpressed in LUAD and eEF2K525me3 levels increase through advancing LUAD disease stages. FAM86A knockdown attenuates LUAD cell proliferation and suppression …

Tsyn-Seq: A T-Cell Synapse-Based Antigen Identification Platform, Yimei Jin, Takahiko Miyama, Alexandria Brown, Tomo Hayase, Xingzhi Song, Licai Huang, Lauren K Mcdaniel, Israel Glover, Taylor M Halsey, Rishika Prasad, Valerie Chapa, Saira Ahmed, Jianhua Zhang, Kunal Rai, Christine B Peterson, Gregory Lizee, Jennifer Karmouch, Eiko Hayase, Jeffrey J Molldrem, Chia-Chi Chang, Wen-Bin Tsai, Robert R Jenq

Faculty, Staff and Student Publications

Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen …

Mdm2 Inhibitors For Cancer Therapy: The Past, Present, And Future, Wei Wang, Najah Albadari, Yi Du, Josef F Fowler, Hannah T Sang, Frank Mckeon, Jia Zhou, Ruiwen Zhang

Faculty, Staff and Student Publications

Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are …

Using Genome And Transcriptome Data From African-Ancestry Female Participants To Identify Putative Breast Cancer Susceptibility Genes, Jie Ping, Guochong Jia, Qiuyin Cai, Xingyi Guo, Ran Tao, Dezheng Huo, Mollie E Barnard, Yu Chen, Montserrat Garcia-Closas, Jian Gu, Jennifer J Hu, Esther M John, Christopher I Li, Katherine Nathanson, Barbara Nemesure, Olufunmilayo I Olopade, Tuya Pal, Michael F Press, Maureen Sanderson, Dale P Sandler, Toshio Yoshimatsu, Prisca O Adejumo, Thomas Ahearn, Abenaa M Brewster, Anselm J M Hennis, Timothy Makumbi, Paul Ndom, Katie M O'Brien, Andrew F Olshan, Mojisola M Oluwasanu, Sonya Reid, Song Yao, Ebonee N Butler, Maosheng Huang, Atara Ntekim, Bingshan Li, Melissa A Troester, Julie R Palmer, Christopher A Haiman, Jirong Long, Wei Zheng

Faculty, Staff and Student Publications

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

Mapping Genotypes To Chromatin Accessibility Profiles In Single Cells, Franco Izzo, Robert M Myers, Saravanan Ganesan, Levan Mekerishvili, Sanjay Kottapalli, Elliot O Eton, Andrew J Dunbar, Robert L Bowman, Jesus Sotelo, Catherine Potenski, Eleni P Mimitou, Maximilian Stahl, Sebastian El Ghaity-Beckley, Joann Arandela, Ramya Raviram, Daniel C Choi, Ronald Hoffman, Ronan Chaligné, Omar Abdel-Wahab, Peter Smibert, Irene M Ghobrial, Joseph M Scandura, Bridget Marcellino, Ross L Levine, Dan A Landau

Faculty, Staff and Student Publications

In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. …

Updates On Who Classification For Small Round Cell Tumors: Ewing Sarcoma Vs Everything Else, Carina A Dehner, Alexander J Lazar, John S A Chrisinger

Faculty, Staff and Student Publications

The WHO Classification of Soft Tissue and Bone Tumours currently recognizes four categories of undifferentiated small round cell sarcoma: Ewing sarcoma, round cell sarcoma with EWSR1-non-ETS fusions including NFATc2 and PATZ1, CIC-rearranged sarcoma, and sarcoma with BCOR genetic alterations. These neoplasms frequently pose significant diagnostic challenges due to rarity and overlapping morphologic and immunohistochemical findings. Further, molecular testing, with accompanying pitfalls, may be needed to establish a definitive diagnosis. This review summarizes the clinical, histologic, immunohistochemical, and molecular features of these neoplasms. In addition, differential diagnosis and areas of uncertainty and ongoing investigation are discussed.

Pet Imaging Of Metabolism, Perfusion, And Hypoxia: Fdg And Beyond, Austin R Pantel, Seong-Woo Bae, Elizabeth J Li, Sophia R O'Brien, H Charles Manning

Faculty, Staff and Student Publications

Imaging glucose metabolism with [18F]fluorodeoxyglucose positron emission tomography has transformed the diagnostic and treatment algorithms of numerous malignancies in clinical practice. The cancer phenotype, though, extends beyond dysregulation of this single pathway. Reprogramming of other pathways of metabolism, as well as altered perfusion and hypoxia, also typifies malignancy. These features provide other opportunities for imaging that have been developed and advanced into humans. In this review, we discuss imaging metabolism, perfusion, and hypoxia in cancer, focusing on the underlying biology to provide context. We conclude by highlighting the ability to image multiple facets of biology to better characterize cancer and …

A Randomized Trial Of Two Remote Health Care Delivery Models On The Uptake Of Genetic Testing And Impact On Patient-Reported Psychological Outcomes In Families With Pancreatic Cancer: The Genetic Education, Risk Assessment, And Testing (Generate) Study, Nicolette J Rodriguez, C Sloane Furniss, Matthew B Yurgelun, Chinedu Ukaegbu, Pamela E Constantinou, Alyson Caruso, Jill E Stopfer, Meghan Underhill-Blazey, Barbara Kenner, Scott H Nelson, Sydney Okumura, Alicia Y Zhou, Tara B Coffin, Hajime Uno, Miki Horiguchi, Allyson J Ocean, Florencia Mcallister, Andrew M Lowy, Alison P Klein, Lisa Madlensky, Gloria M Petersen, Judy E Garber, Scott M Lippman, Michael G Goggins, Anirban Maitra, Sapna Syngal

Faculty, Staff and Student Publications

Background & aims: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes.

Methods: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session …

Benefit Of Axicabtagene Ciloleucel Versus Chemoimmunotherapy In Older Patients And/Or Patients With Poor Ecog Performance Status With Relapsed Or Refractory Large B-Cell Lymphoma After 2 Or More Lines Of Prior Therapy, Matthew A Lunning, Hai-Lin Wang, Zhen-Huan Hu, Frederick L Locke, Tanya Siddiqi, Sairah Ahmed, Yi Lin, Brian T Hill, Armin Ghobadi, Sattva S Neelapu, Jason Westin, Chrisopher Dieyi, Polly Field, Harry Miao, Shilpa A Shahani, Anik Patel, Clare Spooner, Christine Fu, David Muramoto, Hairong Xu, Marcelo C Pasquini

Faculty, Staff and Student Publications

Axicabtagene ciloleucel (axi-cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real-world effectiveness of axi-cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi-cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients …

Noninferiority Of Hypofractionated Vs Conventional Postprostatectomy Radiotherapy For Genitourinary And Gastrointestinal Symptoms: The Nrg-Gu003 Phase 3 Randomized Clinical Trial, Mark K Buyyounouski, Stephanie L Pugh, Ronald C Chen, Mark J Mann, Rajat J Kudchadker, Omar Y Mian, Eric Vigneault, Richard K Valicenti, Maroie Barkati, Colleen A F Lawton, Louis Potters, Drew C Monitto, Jeffrey A Kittel, Thomas M Schroeder, Raquibul Hannan, Casey E Duncan, Joseph P Rodgers, Felix Feng, Howard M Sandler

Faculty, Staff and Student Publications

Importance: No prior trial has compared hypofractionated postprostatectomy radiotherapy (HYPORT) to conventionally fractionated postprostatectomy (COPORT) in patients primarily treated with prostatectomy.

Objective: To determine if HYPORT is noninferior to COPORT for patient-reported genitourinary (GU) and gastrointestinal (GI) symptoms at 2 years.

Design, setting, and participants: In this phase 3 randomized clinical trial, patients with a detectable prostate-specific antigen (PSA; ≥0.1 ng/mL) postprostatectomy with pT2/3pNX/0 disease or an undetectable PSA (< 0.1 ng/mL) with either pT3 disease or pT2 disease with a positive surgical margin were recruited from 93 academic, community-based, and tertiary medical sites in the US and Canada. Between June 2017 and July 2018, a total of 296 patients were randomized. Data were analyzed in December 2020, with additional analyses occurring after as needed.

Intervention: Patients were randomized to receive 62.5 Gy in 25 fractions (HYPORT) or 66.6 Gy in 37 fractions (COPORT).

Main outcomes and measures: The coprimary end points were the 2-year …

Genome-Wide Association Analyses Of Breast Cancer In Women Of African Ancestry Identify New Susceptibility Loci And Improve Risk Prediction, Guochong Jia, Jie Ping, Xingyi Guo, Yaohua Yang, Ran Tao, Stefan Ambs, Yu Chen, Montserrat Garcia-Closas, Jian Gu, Jennifer J Hu, Dezheng Huo, Esther M John, Christopher I Li, James L Li, Katherine L Nathanson, Barbara Nemesure, Olufunmilayo I Olopade, Tuya Pal, Michael F Press, Maureen Sanderson, Dale P Sandler, Xiao-Ou Shu, Melissa A Troester, Song Yao, Prisca O Adejumo, Thomas Ahearn, Abenaa M Brewster, Anselm J M Hennis, Timothy Makumbi, Paul Ndom, Katie M O'Brien, Andrew F Olshan, Mojisola M Oluwasanu, Sonya Reid, Ebonee N Butler, Maosheng Huang, Atara Ntekim, Huijun Qian, Haoyu Zhang, Christine B Ambrosone, Qiuyin Cai, Jirong Long, Julie R Palmer, Christopher A Haiman, Wei Zheng

Faculty, Staff and Student Publications

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Cross-Vendor Multiparametric Mapping Of The Human Brain Using 3d-Qalas: A Multicenter And Multivendor Study, Shohei Fujita, Borjan Gagoski, Ken-Pin Hwang, Akifumi Hagiwara, Marcel Warntjes, Wataru Uchida, Towa Sekine, Rina Tachibana, Tomoya Muroi, Toshiya Akatsu, Akihiro Kasahara, Ryo Sato, Tsuyoshi Ueyama, Christina Andica, Koji Kamagata, Shiori Amemiya, Hidemasa Takao, Yasunobu Hoshino, Yuji Tomizawa, Kazumasa Yokoyama, Berkin Bilgic, Nobutaka Hattori, Osamu Abe, Shigeki Aoki

Faculty, Staff and Student Publications

Purpose: To evaluate a vendor-agnostic multiparametric mapping scheme based on 3D quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS) for whole-brain T1, T2, and proton density (PD) mapping.

Methods: This prospective, multi-institutional study was conducted between September 2021 and February 2022 using five different 3T systems from four prominent MRI vendors. The accuracy of this technique was evaluated using a standardized MRI system phantom. Intra-scanner repeatability and inter-vendor reproducibility of T1, T2, and PD values were evaluated in 10 healthy volunteers (6 men; mean age ± SD, 28.0 ± 5.6 y) who underwent scan-rescan sessions …

The Prognostic Value Of Mek Pathway-Associated Estrogen Receptor Signaling Activity For Female Cancers, Chun Wai Ng, Yvonne T M Tsang, David M Gershenson, Kwong-Kwok Wong

Faculty, Staff and Student Publications

Background: Other than for breast cancer, endocrine therapy has not been highly effective for gynecologic cancers. Endocrine therapy resistance in estrogen receptor positive gynecologic cancers is still poorly understood. In this retrospective study, we examined the estrogen receptor (ER) signaling pathway activities of breast, ovarian, endometrial, and cervical cancers to identify those that may predict endocrine therapy responsiveness.

Methods: Clinical and genomic data of women with breast and gynecological cancers were downloaded from cBioPortal for Cancer Genomics. Estrogen receptor alpha (ESR1) expression level and sample-level pathway enrichment scores (EERES) were calculated to classify patients into four groups (low/high ESR1 and …