Prospective Evaluation of PI-RADS Version 2.1 for Prostate Cancer Detection and Investigation of Multiparametric MRI-derived Markers.
Enis C Yilmaz, M.D., NCI Cancer Research Training Awardee
National Cancer Institute
Dr. Enis C. Yilmaz is a postdoctoral researcher at the Molecular Imaging Branch, National Cancer Institute, with a particular focus on prostate cancer imaging, MRI/US fusion-guided biopsy, and health disparities in prostate cancer. He earned his medical degree in 2021 on a full scholarship from Bahcesehir University (Istanbul, Türkiye). During his studies, Dr. Yilmaz gained diverse clinical experience through rotations in Italy and Taiwan and engaged in research at Harvard Medical School and UCLA as a visiting researcher. Dr. Yilmaz is investigating AI algorithms to enhance diagnostic accuracy and patient management in prostate cancer under Dr. Baris Turkbey’s guidance. Dr. Yilmaz serves as an Associate Editor on the Radiology In Training Editorial Board, and he is an active member of RSNA, ARRS, ACR, and SAR. Currently pursuing a residency in diagnostic radiology, he aims to combine his research skills with his developing clinical experience as a future physician-scientist.
In our study, we assessed the Prostate Imaging Reporting and Data System (PI-RADS), version 2.1, which is a continually developing and internationally acknowledged MRI-based scoring system used for evaluating the risk of prostate cancer. Conducted between April 2019 and December 2021, our prospective study focused on biological males with suspected or known prostate cancer, aiming to determine the effectiveness of PI-RADS 2.1 in conjunction with MRI features like lesion size, shape, and volume for detecting clinically significant prostate cancer. Apart from assessing the cancer yield in each PI-RADS category, another aspect of our work was to identify more objective, measurable criteria for lesion shape and volume, moving beyond the subjective parameters currently used in PI-RADS. We discovered that the likelihood of identifying clinically significant prostate cancer increases with higher PI-RADS categories and that quantifiable MRI features, such as lesion volume and measure of roundness, are predictors of significant cancer. Our findings also highlight that merging certain subcategories in PI-RADS might result in unnecessary biopsies. In conclusion, our research suggests that incorporating the objective lesion imaging criteria into patient care, alongside PI-RADS scores, could improve diagnostic accuracy. If validated in further studies, these objective measures could potentially be integrated into future iterations of PI-RADS, offering a more precise and reliable approach to prostate cancer detection and reducing unnecessary interventions.
Gilbert Rahme (pronounced the French way: Jill-bear Ra-hmme) was born and raised in Beirut, Lebanon. After earning a Bachelor's degree at the Lebanese University and a Master's degree in Science at the American University of Beirut, Gilbert joined Mark Israel's laboratory at Dartmouth for his Ph.D., focusing on signaling pathways underlying brain tumor pathology. He then joined Bradley Bernstein's laboratory at Harvard Medical School for his postdoctoral research, focusing on brain tumor epigenetics. Gilbert has been continuously funded by the NCI since his postdoctoral training, receiving both an F32 postdoctoral fellowship and a K99/R00 transition award. Following his latest publication in the journal Cell, Gilbert initiated his own laboratory at Stony Brook University and Cancer Center, where his laboratory focuses on brain tumor epigenetics.
Diffuse gliomas are the most common malignant primary brain tumors and remain incurable despite aggressive multimodal therapies. Understanding the mechanisms by which gliomas arise is a critical step towards improved therapies. Missense mutations in the metabolic enzyme Isocitrate Dehydrogenase 1 (IDH1) drive a subtype of diffuse gliomas with genome-wide DNA hypermethylation, termed the G-CIMP hypermethylator profile. This profile is caused by mutant IDH1 (IDH1mut) enzyme, which produces 2-hydroxyglutarate (2-HG), an oncometabolite inhibitor of the ten-eleven translocation (TET) demethylases. DNA hypermethylation may promote gliomagenesis by silencing tumor suppressor genes or, alternatively, by activating proto-oncogenes through disruption of CCCTC-binding factor (CTCF) insulators. CTCF insulator sites define the three-dimensional shape of the genome by dictating the boundaries of topologically associating domains (TADs). Enhancers and promoters can interact when located in the same TAD but are restricted from interacting across different TADs. In IDH1mut gliomas, CpG dinucleotides around CTCF binding sites are frequently methylated, effectively compromising CTCF binding and thus TAD organization. Importantly, the effects of TAD reorganization on gene expression are contingent on enhancers, which are cell-type specific.
To determine the epigenetic changes that fuel gliomagenesis, we employed a multi-omic approach on clinical IDH1mut glioma samples, leveraging methylation, transcription factor DNA binding, and gene expression analyses. We found a CTCF insulator near the Platelet-derived Growth Factor Receptor A (PDGFRA) proto-oncogene that is recurrently disrupted by methylation. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. We show that a second lesion, methylation-dependent silencing of the Cyclin-dependent Kinase Inhibitor 2A (Cdkn2a) tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Our study demonstrates the capacity of recurrent epigenetic lesions to drive gliomagenesis.
Ana P. Gomes is an Assistant Member of the Department of Molecular Oncology at the Moffitt Cancer Center. She received a PhD in Cell and Molecular Biology from the University of Coimbra and did her PhD work under the supervision of Dr. David Sinclair at Harvard Medical School studying the role of NAD+ in skeletal muscle aging. She completed her postdoctoral training with Dr. John Blenis at Weill Cornell Medicine, studying the influence of age-driven metabolic and epigenetic reprogramming in tumor progression. Her laboratory aims to define how aging shapes the tumorigenic process spanning from signaling paradigms to epigenetic reprogramming and metabolic rewiring. Ana has received a Susan G. Komen postdoctoral fellowship, a K99/R00 Pathway to Independence Award, the Tri-Institutional Breakout Prize, an American Cancer Society Scholar Award and was selected as a Forbeck Scholar, a STAT Wunderkind and a Rising Star in Cancer Metabolism and Signaling by the NYAS.
The reprogramming of cellular metabolism for both the development of cancer and its progression to metastasis presents a ripe area of research. Far from simply existing as the process of breakdown and buildup of nutrients in the cell, cellular metabolism has become recognized as a fundamental determinant of cellular identity and function. It is now evident that certain metabolites can drive cancer progression and metastasis, functioning in autocrine, paracrine and endocrine fashions. We have previously demonstrated how a systemic age-induced increase of a single metabolite, contributes to poor cancer prognosis and increased cancer-related mortality in elderly patients, highlighting the importance of metabolic alterations in determining tumor progression. Building on these findings, we have identified that production of this age-related metabolite occurs in cancer cells through deregulation of its biosynthetic pathway and elicits a transcriptional reprogramming that enables cancer cells to attain the traits necessary for progression into metastatic disease.
“Chondroitin Sulfate Proteoglycans Are De Facto Cellular Receptors for Human Papillomavirus 16 under High Serum Conditions"
Dr. Nathan Fons, NCI Cancer Research Training Awardee
National Cancer Institute
Dr. Nathan Fons did his undergraduate studies at the University of Wisconsin-Madison and then went on to get a Ph.D. in Experimental Pathology from Yale University. Nathan is currently a postdoctoral research fellow under the mentorship of Dr. John Schiller in the Laboratory of Cellular Oncology at the NCI. His work investigates the binding interactions of human papillomaviruses with host cells and hopes to answer key questions in the field relating to the initial binding and entry receptors for these viruses. Using a variety of approaches including high content microscopy, CRISPR-screening, and bioinformatic tools, this work has implications spanning the fields of basic virology, cell biology, and glycobiology. Expanding on this work, Nathan is also actively involved in the characterization of Belzupacap sarotalocan, an investigational tumor-targeted therapy derived from human papillomavirus capsids, to better define biological signatures mediating its effectiveness.
Heparan sulfate proteoglycans (HSPGs) have previously been identified as the predominant host attachment factors used by human papillomaviruses (HPVs) prior to infection. Here, we demonstrate that in vitro, HPV binding to HSPGs is strongly dependent on the surrounding experimental conditions, including the concentration of fetal bovine serum (FBS). We found that high concentrations of FBS can block HSPG-binding sites and cause a dependence on sulfated chondroitin sulfate proteoglycans (CSPGs) as alternative initial viral receptors. Further, we demonstrate that use of a human-derived alternative to FBS, human platelet lysate, also occludes HSPG-dependent binding, causing a shift toward CSPGs for viral attachment. As HPV infection of basal epithelial cells is thought to occur at sites of microtrauma with exposure to high serum levels and platelet factors, these unexpected findings highlight a possible role for CSPGs as important cellular receptors for the binding and infectivity of HPV in vivo.
Dr. Róża Kamila Przanowska is a Polish molecular biologist. She obtained Bachelor and Master of Science degrees in biotechnology at University of Warsaw (Warsaw, Poland). She was a Summer Intern in Max Planck Institute (Bad Nauheim, Germany) and a Fulbright Scholar at University of Virginia (Charlottesville, USA). In 2021 she defended her dissertation entitled “Essentiality and functional importance of short and long non-coding RNAs in myogenesis” in the lab of Dr. Anindya Dutta at University of Virginia. During her PhD studies she was awarded among others the American Heart Association Predoctoral Fellowship, Graduate Biosciences Society Student Leadership Award, and F99/K00 NCI Predoctoral to Postdoctoral Fellow Transition Award. She is currently a Research Associate in Dr. Kevin Janes’s laboratory at University of Virginia working on non-coding RNA heterogeneity in breast cancer.
She is married to the Polish molecular biologist and HEMA fencer Dr. Piotr Przanowski. They have three kids.
Long non-coding RNAs (lncRNA) are a type of RNA that is not translated into protein. Many lncRNAs have been discovered using high-throughput sequencing data; however, it is unclear what fraction of them is functional and what structural properties affect their phenotype. One of the lncRNAs important for skeletal muscle differentiation is MUNC acting in cis as an enhancer RNA for the Myod1 gene and in trans by recruiting the cohesin complex. Here, experimental probing of the RNA structure revealed that MUNC contains multiple structural domains not detected by prediction algorithms in the absence of experimental information. We show that these specific and structurally distinct domains are required for induction of muscle-related genes, for binding genomic sites and gene expression regulation, and for binding the cohesin complex. Our study reveals unexpectedly complex, structure-driven functions for the MUNC and emphasizes the importance of experimentally determined structures for understanding structure-function relationships in lncRNAs.
“Immune cell gene expression signatures in diffuse glioma are associated with IDH mutation status, patient outcome and malignant cell state, and highlight the importance of specific cell subsets in glioma biology”
Dr. Bharati Mehani, NCI Cancer Research Training Awardee
National Cancer Institute
Bharati Mehani, PhD is a senior Postdoctoral Fellow at NCI, NIH. She was first introduced to the amazing field of bioinformatics and its application in science in 2011 when she joined her masters at BHU, Varanasi, and there has been no going back since then. She received her early training at Dr. Mukhopadhyay’s lab in 2011 at IGIB, New Delhi, India where she joined his group as a Project Assistant to study comparative genomics using spectrum of CNVs, somatic mosaicism and non-coding RNAs in human brain. In 2014, she enrolled for Ph.D. program at the same lab where her research interest was to study transcriptomics changes in human brain mediated by fusion transcripts and RNA editing. In December 2018, she joined Dr. Aldape’s lab at NCI as a visiting fellow to investigate the regulatory landscape of gliomas by integrating single cell RNA Seq with deconvolved bulk tumors and other multi-omics.
This presentation will discuss the biological and clinical significance of the immune cell environment related to IDH mutation status, patient prognosis and the mesenchymal state in diffuse gliomas.
The tumor micro-environment (TME) plays critical role in various cancers, including gliomas. We estimated immune cell type-specific gene expression profiles in glioma datasets and found estimated proportions and gene expression profiles that varied according to IDH mutation status. Cluster-of-cluster analyses of immune cell gene expression identified groups with distinct survival outcomes in IDH-WT and IDH-MUT tumors. We verified these findings by applying a signature matrix derived from single-cell RNA Seq data. To link immune cell signatures with outcomes in checkpoint therapy, we found a significant association of monocytic gene expression clusters with patient survival and with mesenchymal scores. Integrating immune cell-based gene expressions with previously described malignant cell states in glioma demonstrated that macrophage M0 abundance significantly correlated with mesenchymal state in IDH-WT gliomas. Overall, these results highlight biological and clinical significance of immune cell environment related to IDH mutation status, patient prognosis and the mesenchymal state in diffuse gliomas.
Jennifer Moss, PhD, is an Assistant Professor in the Departments of Family and Community Medicine and Public Health Sciences at Penn State College of Medicine. She also serves as Assistant Director of Data and Analysis in the Office of Cancer Health Equity at the Penn State Cancer Institute. Dr. Moss received her PhD in Health Behavior at the University of North Carolina, Chapel Hill, and she served as a post-doctoral Cancer Prevention Fellow at the National Cancer Institute. Dr. Moss is a social and behavioral scientist focused on geographic disparities in the cancer control continuum. Her work examines aspects of the social and built environment that impact health and healthcare outcomes relevant to cancer, with a special interest in underserved and rural communities. Dr. Moss has published more than 60 peer-reviewed manuscripts and has an extensive history of teaching and service.
Counties with higher levels of poverty since 1980 (“persistent poverty”) tend to be rural and racially diverse, but it is not clear how poverty, rurality, and race work together to influence trends in cancer mortality. We analyzed cancer deaths from 1990-1992 and 2014-2018. During each time period, compared to other counties, persistent poverty counties had about 12 excess cancer deaths per 100,000 people per year (1990-1992: 12.7, 95% confidence interval[CI]=11.4-14.1; 2014-2018: 11.0, 95% CI=10.2-11.8). Over time, disparities by persistent poverty widened for colorectal and breast cancers, but they were stable or mixed for the remaining cancer types. The highest mortality rates were observed among African American or Black residents of rural, persistent poverty counties for colorectal, oropharyngeal, breast, cervical, and prostate cancers. Since several factors influence cancer mortality, a multi-faceted approach is needed to improve outcomes in persistent poverty counties.
"Are beliefs about the importance of genetics for cancer prevention and early detection associated with high risk cancer genetic testing in the U.S. Population?"
Dr. Sukh Makhnoon, K99/R00 Awardee
University of Texas Southwestern Medical Center
Sukh Makhnoon is an Assistant Professor at the Peter O’Donnell School of Public Health and Simmons Comprehensive Cancer Center at UT Southwestern Medical Center. Dr. Makhnoon is a genetic epidemiologist who focuses on public health genomics and the translation of genomic applications into clinical practice. Her research uses genetics, behavioral science, epidemiology, health services, and clinical perspectives to improve utilization of cancer prevention and control innovations across the cancer continuum, with a focus on uncertain and reclassified genetic test results. Her research interests include uncertainty related to genomic sequencing, genomic variant reclassification, and patients’ experiences with genomic sequencing. Prior to joining UTSW, Dr. Makhnoon was a postdoctoral fellow at UT MD Anderson Cancer Center in the Division of Cancer Prevention and Population Sciences. She received her PhD in Public Health Genetics and MS in Genetic Epidemiology from the University of Washington in Seattle.
Public attitudes towards germline genetic testing for inherited cancers have been found to be generally positive. We know that diverse causal beliefs about cancer and sociodemographic factors are associated with uptake of cancer genetic testing. However, it is unclear how beliefs about genetically informed cancer prevention and genetically informed early detection of cancer shape testing behaviors. Using data from the National Health Information National Trends Survey, we studied this relationship between belief about cancer genetics and participation in cancer genetic testing. Interestingly, we find that belief in the importance of genetics for early detection of cancer was associated with testing however, belief in the importance of genetics for cancer prevention was not. The pattern of association is a surprising finding that warrants further investigation as better understanding cancer prevention beliefs and their impact on genetic test uptake may inform population genetic testing efforts.
Dr. Daniel Arango is an Assistant Professor in the Department of Pharmacology and the Robert H. Lurie Comprehensive Cancer Center at Northwestern University. His research program investigates how chemical modifications of RNA regulate protein synthesis and how this interplay affects cell fate decisions such as cell proliferation, cell differentiation, and cell death in cancer. Dr. Arango received a B.S. in Biology from Universidad de Antioquia – Colombia, obtained a Ph.D. in Molecular Biology from The Ohio State University, and conducted postdoctoral training in RNA biology at the U.S. National Cancer Institute.
The Arango lab works to unravel the molecular mechanisms by which post-transcriptional modifications of RNA regulate mRNA processing, stability, and translation and how this interplay affects cell fate decisions in homeostasis and disease. With more than 150 ribonucleotide modifications in all classes of RNA, the epitranscriptome has become a crucial regulatory layer of gene expression regulation. Although the vast diversity of RNA modifications entails an immense regulatory potential, deciphering the epitranscriptome is an enormous scientific challenge. Yet, its decryption will reveal fundamental aspects of gene expression regulation during normal metabolism and disease, which can potentially be leveraged for therapeutic applications. This seminar will focus on our recent findings that acetylation of cytidines in RNA regulates translation in a position-specific manner and the Arango’s laboratory ongoing studies to determine the mechanisms by which the RNA acetyltransferase complexes promote cell proliferation and cancer growth.
"Utilizing Multiple Strategies to Advance Equitable Implementation of Lung Cancer Screening: Implications of Varying Eligibility Criteria by Race and Ethnicity"
Dr. Randi Williams, K99/R00 Awardee
Randi M. Williams, PhD, MPH is an Assistant Professor in the Department of Oncology and a member of the Cancer Prevention and Control Program within the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center. Her research focuses on methods to promote the adoption of evidence-based lung cancer control practices to advance health equity.
Dr. Williams’s research utilizes multilevel approaches to promote equitable care within the healthcare setting. In her ongoing National Cancer Institute-funded K99/R00, Dr. Williams is targeting provider and patient behavior to promote patient-provider communication about lung cancer screening and to advance equity in screening rates between Black and White patients.
Dr. Williams completed her postdoctoral fellowship at Lombardi under a Diversity Supplement. She received her PhD from the University of Maryland, College Park, School of Public Health, her MPH in behavioral sciences and health education from Emory University and a BA degree in psychology from Syracuse University.
In 2013, lung cancer screening (lung screening) was recommended for high-risk individuals. The annual rate of lung screening has risen slowly, particularly among Black individuals. In part, this racial disparity resulted in expanded 2021 screening criteria. Methods: Survey data were used to: 1) describe the number of people screened in 2019, 2) compare the percent eligible for lung screening using the 2013 versus the 2021 guidelines, and 3) determine the percent eligible using more detailed criteria. Results: Lung screening rates increased in 2019, and the 2021 criteria will result in more individuals eligible for screening. Using additional criteria may identify more individuals eligible for lung screening. Conclusions: This presentation will discuss ways to include more individuals who may benefit from lung screening and other strategies that can improve screening rates in an equitable manner
Tarsha Jones, PhD, MSN, RN, PHNA-BC, is an Assistant Professor of Nursing at Florida Atlantic University. She obtained a Bachelor’s of Science in Nursing Degree from Seton Hall University, a Master’s of Science in Community/Public Health Nursing from the Catholic University of America, with a specialization in immigrants, refugees, and global health. She is a board certified advanced public health nurse (PHNA-BC). She obtained a Doctor of Philosophy (PhD) in Nursing degree from Duquesne University and completed a post-doctoral research fellowship at Dana Farber Cancer Institute and Harvard Medical School. Dr. Jones’s research focuses on breast cancer prevention and control and reducing cancer health disparities. She has been a champion for vulnerable underserved populations and promoting health equity. Dr. Jones is a member of Sigma, an International Nursing Honor Society and the International Nursing CASCADE Consortium.
This presentation will discuss preliminary observations from a survey of diverse young breast cancer survivors.
"Exploring the Role of Masculine Role Norms, Medical Mistrust, and Normative Support on Colorectal Cancer Screening Uptake among African-American Men"
Dr. Charles R. Rogers, K01 Awardee
Medical College of Wisconsin
Dr. Charles R. Rogers is an Associate Professor in the Institute for Health & Equity at the Medical College of Wisconsin (MCW), an MCW Cancer Center Research Scholar Endowed Chair, and the inaugural Associate Director of Community Outreach & Engagement at MCW’s Cancer Center. He is also the Founding Director of his Men’s Health Inequities Research Lab and an Associate Member of the University of Michigan Mixed Methods Program. He is committed to dismantling systems of oppression to ensure equitable health for all. His transdisciplinary training in applied mathematics and statistics, health education, public health administration and policy, community-based participatory research, and cancer-related health disparities provides a unique perspective on translating research findings into effective approaches to disease prevention. For more than 20 years, Dr. Rogers has shared his knowledge across the world and via numerous media outlets. To learn more, visit crrogersPhD.com or follow Dr. Rogers on Twitter: @crrogersPhD.
Among all racial and ethnic groups, African-American men are the most likely to get colorectal cancer (CRC) and to die of it. Screening can prevent CRC and save lives, but few African-American men receive a CRC screening test. This study recruited English-speaking African-American men aged 45 to 75 into focus groups to examine how their attitudes, beliefs, and life circumstances affected their likelihood of getting a CRC screening test. These focus groups revealed two important barriers for these African-American men to getting screened for CRC: the way they thought about the social expectations of being a man and their mistrust of doctors. The researchers concluded that healthcare professionals need to find ways to address these barriers when they develop programs aimed at encouraging African-American men to get screened for CRC.
Dr. Chris Gibson graduated from Yale University School of Medicine in 2009 and trained in internal medicine at Brigham and Women's Hospital, where he was also chief medical resident. He completed his oncology and hematology fellowships at Dana-Farber Cancer Institute in 2017. His research focuses on how genetic mutations in the blood cells of bone marrow transplant donors and recipients affect recipient outcomes.
Clonal hematopoiesis (CH) can be transmitted from a donor to a recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain. We performed targeted error-corrected sequencing on samples from 1,727 donors age 40 years or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant. We found that donor CH is closely associated with clinical outcomes in transplant recipients, with differential impact on graft alloimmune function and potential for leukemic transformation related to mutated gene and somatic clonal abundance. Donor DNMT3A-CH is associated with improved recipient survival because of reduced relapse risk and with an augmented network of inflammatory cytokines in recipients. Risk of donor cell leukemia in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome–associated mutations or germline predisposition in donors.
Dr. Ajit Johnson Nirmal is a postdoctoral fellow with Dr. Peter Sorger and Dr. David Weinstock at the Harvard Medical School and Dana Farber Cancer Institute. Dr. Nirmal studies the role of tumor microenvironment in tumor development and drug resistance. By computational integration of highly multiplexed imaging data with omics data, Dr. Nirmal aims to decipher regulatory circuits that underlie cancer development and drug resistance, with a goal of building dynamic personalized medicine frameworks that will generate clinically actionable therapeutic insights for individual patients.
Melanoma is a type of skin cancer that can be cured if caught early but can be life-threatening if it spreads. In this study, we used a combination of imaging and sequencing technology to study how melanoma interacts with its microenvironment. We found that the organization of cancer cells, immune cells, and other cells in the body changes as melanoma progresses. In early stages, there are signs that the immune system is being suppressed. When melanoma becomes invasive, specific areas form where the immune system is suppressed, and cancer cells can grow and spread. However, a short distance away, there are also areas where the immune system fights cancer. This shows that cancer and the immune system can coexist and evolve together. This type of study helps understand how cancer can avoid being destroyed by the immune system.