Genetic Processes Commons^™

Advancing Novel Contrast Agents For Applications In Fluorescence-Guided Neurosurgery Using Fluorescence Cryotomography, Augustino Vittorio Scorzo

Dartmouth College Ph.D Dissertations

Fluorescence guided surgery (FGS) is an emerging surgical technique that aims to help surgeons identify tissue types to assist in surgical decision making - ideally providing “cut-by-color” guidance. A primary application for this approach is the identification of tumor tissue to achieve more accurate and complete tumor removal while simultaneously minimizing damage to surrounding normal tissue. The cornerstone of tumor visualization for FGS is the administration of fluorescent contrast agents, or in some cases metabolic precursors, designed to accumulate specifically in tumor tissue, and a wide range of agents that use different targeting mechanisms are currently under investigation. Although these …

Elucidating The Multi-Omics Of Early-Onset Colorectal Cancer, Jumanah Alshenaifi

Dissertations and Theses (Open Access)

The incidence and mortality rates of sporadic early-onset colorectal cancer have increased in recent decades, but there is no clear etiological basis for this trend. EOCRC is commonly defined as colon and rectal cancers diagnosed before the age of 50 years. The rising incidence of EOCRC has made it the second most common cancer and the third leading cause of cancer death in this age group. The rising incidence of EOCRC is also documented internationally in more than 20 countries across different continents. Clinically, EOCRC has a distinct, more aggressive clinical profile than LOCRC. While approximately 15% of EOCRC cases …

Update On Cancer And Central Nervous System Tumor Surveillance In Pediatric Nf2-, Smarcb1-, And Lztr1-Related Schwannomatosis, Melissa R Perrino, Marjolijn C J Jongmans, Gail E Tomlinson, Mary-Louise C Greer, Sarah R Scollon, Sarah G Mitchell, Jordan R Hansford, Kris Ann P Schultz, Wendy K Kohlmann, Jennifer M Kalish, Suzanne P Macfarland, Anirban Das, Kara N Maxwell, Stefan M Pfister, Rosanna Weksberg, Orli Michaeli, Uri Tabori, Gina M Ney, Philip J Lupo, Jack J Brzezinski, Douglas R Stewart, Emma R Woodward, Christian P Kratz

Faculty, Staff and Students Publications

Schwannomatosis (SWN) is a distinct cancer predisposition syndrome caused by germline pathogenic variants in the genes NF2, SMARCB1, or LZTR1. There is a significant clinical overlap between these syndromes with the hallmark of increased risk for cranial, spinal, and peripheral schwannomas. Neurofibromatosis type 2 was recently renamed as NF2-related SWN and is the most common SWN syndrome, with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas, and less commonly, ependymoma. SMARCB1-related SWN is a familial SWN syndrome associated with peripheral and spinal schwannomas and an increased risk for meningiomas and malignant peripheral nerve sheath tumors, even in the absence …

Genomic Insights For Personalised Care In Lung Cancer And Smoking Cessation: Motivating At-Risk Individuals Toward Evidence-Based Health Practices, Tony Chen, Giang Pham, Louis Fox, Nina Adler, Xiaoyu Wang, Jingning Zhang, Jinyoung Byun, Younghun Han, Gretchen R B Saunders, Dajiang Liu, Michael J Bray, Alex T Ramsey, James Mckay, Laura J Bierut, Christopher I Amos, Rayjean J Hung, Xihong Lin, Haoyu Zhang, Li-Shiun Chen

Faculty, Staff and Students Publications

BACKGROUND: Lung cancer and tobacco use pose significant global health challenges, necessitating a comprehensive translational roadmap for improved prevention strategies such as cancer screening and tobacco treatment, which are currently under-utilised. Polygenic risk scores (PRSs) may further motivate health behaviour change in primary care for lung cancer in diverse populations. In this work, we introduce the GREAT care paradigm, which integrates PRSs within comprehensive patient risk profiles to motivate positive health behaviour changes.

METHODS: We developed PRSs using large-scale multi-ancestry genome-wide association studies and standardised PRS distributions across all ancestries. We validated our PRSs in 561,776 individuals of diverse ancestry …

Atr Inhibition Radiosensitizes Cells Through Augmented Dna Damage And G2 Cell Cycle Arrest Abrogation, Scott J Bright, Mandira Manandhar, David B Flint, Rishab Kolachina, Mariam Ben Kacem, David Kj Martinus, Broderick X Turner, Ilsa Qureshi, Conor H Mcfadden, Poliana C Marinello, Simona F Shaitelman, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Ataxia telangiectasia and Rad3-related protein (ATR) is a key DNA damage response protein that facilitates DNA damage repair and regulates cell cycle progression. As such, ATR is an important component of the cellular response to radiation, particularly in cancer cells, which show altered DNA damage response and aberrant cell cycle checkpoints. Therefore, ATR's pharmacological inhibition could be an effective radiosensitization strategy to improve radiotherapy. We assessed the ability of an ATR inhibitor, AZD6738, to sensitize cancer cell lines of various histologic types to photon and proton radiotherapy. We found that radiosensitization took place through persistent DNA damage and abrogated G2 …

Reconstructing Oral Cavity Tumor Evolution Through Brush Biopsy, Evit John, Tom Lesluyes, Toby M Baker, Maxime Tarabichi, Ann Gillenwater, Jennifer R Wang, Peter Van Loo, Xiao Zhao

Faculty, Staff and Student Publications

Oral potentially malignant disorders (OPMDs) with genomic alterations have a heightened risk of evolving into oral squamous cell carcinoma (OSCC). Currently, genomic data are typically obtained through invasive tissue biopsy. However, brush biopsy is a non-invasive method that has been utilized for identifying dysplastic cells in OPMD but its effectiveness in reflecting the genomic landscape of OPMDs remains uncertain. This pilot study investigates the potential of brush biopsy samples in accurately reconstructing the genomic profile and tumor evolution in a patient with both OPMD and OSCC. We analyzed single nucleotide variants (SNVs), copy number aberrations (CNAs), and subclonal architectures in …

Hif-2Α-Dependent Induction Of Mir-29a Restrains Th1 Activity During T Cell Dependent Colitis, Agnieszka K Czopik, Eóin N Mcnamee, Victoria Vaughn, Xiangsheng Huang, In Hyuk Bang, Trent Clark, Yanyu Wang, Wei Ruan, Tom Nguyen, Joanne C Masterson, Eunyoung Tak, Sandra Frank, Colm B Collins, Howard Li, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Mark E Gerich, Glenn T Furuta, Xiaoyi Yuan, Anil K Sood, Edwin F De Zoeten, Holger K Eltzschig

Faculty, Staff and Student Publications

Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4+ T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4+ T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target …

Whole Genome And Reverse Protein Phase Array Landscapes Of Patient Derived Osteosarcoma Xenograft Models, Chia-Chin Wu, Licai Huang, Zhongting Zhang, Zhenlin Ju, Xingzhi Song, E Anders Kolb, Wendong Zhang, Jonathan Gill, Min Ha, Malcolm A Smith, Peter Houghton, Christopher L Morton, Raushan Kurmasheva, John Maris, Yael Mosse, Yiling Lu, Richard Gorlick, P Andrew Futreal, Hannah C Beird

Faculty, Staff and Student Publications

Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds …

The Icf Syndrome Protein Cdca7 Harbors A Unique Dna Binding Domain That Recognizes A Cpg Dyad In The Context Of A Non-B Dna, Swanand Hardikar, Ren Ren, Zhengzhou Ying, Jujun Zhou, John R Horton, Matthew D Bramble, Bin Liu, Yue Lu, Bigang Liu, Luis Della Coletta, Jianjun Shen, Jiameng Dan, Xing Zhang, Xiaodong Cheng, Taiping Chen

Faculty, Staff and Student Publications

CDCA7, encoding a protein with a carboxyl-terminal cysteine-rich domain (CRD), is mutated in immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a disease related to hypomethylation of juxtacentromeric satellite DNA. How CDCA7 directs DNA methylation to juxtacentromeric regions is unknown. Here, we show that the CDCA7 CRD adopts a unique zinc-binding structure that recognizes a CpG dyad in a non-B DNA formed by two sequence motifs. CDCA7, but not ICF mutants, preferentially binds the non-B DNA with strand-specific CpG hemi-methylation. The unmethylated sequence motif is highly enriched at centromeres of human chromosomes, whereas the methylated motif is distributed throughout …

Regulatory Complexity Of Cellular Differentiation In Candida Albicans Revealed Through Systematic Screening Of Protein Kinase Mutants, Michael C Lorenz

Faculty, Staff and Student Publications

A recent study in mBio reports the construction and preliminary screening of a library containing mutants of 99 of the 119 predicted protein kinases in Candida albicans (the majority of the remaining 20 are probably essential) (J. Kramara, M.-J. Kim, T. L. Ollinger, L. C. Ristow, et al., mBio e01249-24, 2024, https://doi.org/10.1128/mbio.01249-24). Using a quantitative competition assay in 10 conditions that represent nutritional, osmotic, cell wall, and pH stresses that are considered to model various aspects of the host environment allowed them to phenotypically cluster kinases, which highlight both the integration and specialization of signaling pathways, suggesting novel functions …

The Dna Methylome Of Pediatric Brain Tumors Appears Shaped By Structural Variation And Predicts Survival, Fengju Chen, Yiqun Zhang, Lanlan Shen, Chad J Creighton

Faculty, Staff and Students Publications

Structural variation heavily influences the molecular landscape of cancer, in part by impacting DNA methylation-mediated transcriptional regulation. Here, using multi-omic datasets involving >2400 pediatric brain and central nervous system tumors of diverse histologies from the Children's Brain Tumor Network, we report hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of somatic structural variant (SV) breakpoints is recurrently associated with altered expression or DNA methylation, respectively, including tumor suppressor genes ATRX and CDKN2A. Altered DNA methylation near enhancers associates with nearby somatic SV breakpoints, including MYC and MYCN. A subset of genes with SV-CGI methylation associations …

Dna Fork Remodeling Proteins, Zranb3 And Smarcal1, Are Uniquely Essential For Aging Hematopoiesis, Saul Kushinsky, Matthew V. Puccetti, Clare M. Adams, Irina Shkundina, Nikkole James, Brittany M. Mahon, Peter Michener, Christine M. Eischen

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Over a lifetime, hematopoietic stem and progenitor cells (HSPCs) are forced to repeatedly proliferate to maintain hematopoiesis, increasing their susceptibility to DNA damaging replication stress. However, the proteins that mitigate this stress, protect HSPC replication, and prevent aging-driven dysregulation are unknown. We report two evolutionarily conserved, ubiquitously expressed chromatin remodeling enzymes with similar DNA replication fork reversal biochemical functions, Zranb3 and Smarcal1, have surprisingly specialized roles in distinct HSPC populations. While both proteins actively mitigate replication stress and prevent DNA damage and breaks during lifelong hematopoiesis, the loss of either resulted in distinct biochemical and biological consequences. Notably, defective long-term …

14-3-3Ζ Suppresses Rankl Signaling By Destabilizing Traf6, R. Ayyasamy, S. Fan, P. Czernik, B. Lecka-Czernik, Somsubhra Chattopadhyay, R. Chakravarti

Markey Cancer Center Faculty Publications

Macrophages are essential regulators of inflammation and bone loss. Receptor activator of nuclear factor-κβ ligand (RANKL), a pro-inflammatory cytokine, is responsible for macrophage differentiation to osteoclasts and bone loss. We recently showed that 14-3-3ζ-knockout (Ywhaz^KO) rats exhibit increased bone loss in the inflammatory arthritis model. 14-3-3ζ is a cytosolic adaptor protein that actively participates in many signaling transductions. However, the role of 14-3-3ζ in RANKL signaling or bone remodeling is unknown. We investigated how 14-3-3ζ affects osteoclast activity by evaluating its role in RANKL signaling. We utilized 14-3-3ζ-deficient primary bone marrow–derived macrophages obtained from wildtype and Ywhaz^{KO …}

Multiple Omics Levels Of Chronic Lymphocytic Leukemia, Aleksander Turk, Eva Čeh, George A Calin, Tanja Kunej

Faculty, Staff and Student Publications

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy characterized by the proliferation of functionally mature but incompetent B cells. It is the most prevalent type of leukemia in Western populations, accounting for approximately 25% of new leukemia cases. While recent advances, such as ibrutinib and venetoclax treatment have improved patient outlook, aggressive forms of CLL such as Richter transformation still pose a significant challenge. This discrepancy may be due to the heterogeneity of factors contributing to CLL development at multiple -omics levels. However, information on the omics of CLL is fragmented, hindering multi-omics-based research into potential treatment options. To address …

Durable Objective Response To Lurbinectedin In Small Cell Bladder Cancer With Tp53 Mutation: A Molecular-Directed Strategy, Mohammad Jad Moussa, Jaanki Khandelwal, Nathaniel R Wilson, Sagar A Naik, Vivek Subbiah, Matthew T Campbell, Pavlos Msaouel, Parminder Singh, Omar Alhalabi

Faculty, Staff and Student Publications

Small cell bladder cancer (SCBC) is a rare and aggressive disease, often treated with platinum/etoposide-based chemotherapy. Key molecular drivers include the inactivation of onco-suppressor genes (TP53, RB1) and amplifications in proto-oncogenes (MYC). We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A genomic analysis of a metastatic biopsy prior to lurbinectedin initiation revealed a TP53 mutation and amplification of the cell cycle regulators E2F3 and MYCL. A repeat biopsy following …

An Essential Gene Signature Of Breast Cancer Metastasis Reveals Targetable Pathways, Yiqun Zhang, Fengju Chen, Marija Balic, Chad J Creighton

Faculty, Staff and Students Publications

BACKGROUND: The differential gene expression profile of metastatic versus primary breast tumors represents an avenue for discovering new or underappreciated pathways underscoring processes of metastasis. However, as tumor biopsy samples are a mixture of cancer and non-cancer cells, most differentially expressed genes in metastases would represent confounders involving sample biopsy site rather than cancer cell biology.

METHODS: By paired analysis, we defined a top set of differentially expressed genes in breast cancer metastasis versus primary tumors using an RNA-sequencing dataset of 152 patients from The Breast International Group Aiming to Understand the Molecular Aberrations dataset (BIG-AURORA). To filter the genes …

Update On Cancer Predisposition Syndromes And Surveillance Guidelines For Childhood Brain Tumors, Jordan R Hansford, Anirban Das, Rose B Mcgee, Yoshiko Nakano, Jack Brzezinski, Sarah R Scollon, Surya P Rednam, Jaclyn Schienda, Orli Michaeli, Sun Young Kim, Mary-Louise C Greer, Rosanna Weksberg, Douglas R Stewart, William D Foulkes, Uri Tabori, Kristian W Pajtler, Stefan M Pfister, Garrett M Brodeur, Junne Kamihara

Faculty, Staff and Students Publications

Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease etiology increases. Some children with brain tumors may present with nonmalignant phenotypic features of specific syndromes (e.g., nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch-repair deficiency), while others may present with a strong family history of cancer (e.g., Li-Fraumeni syndrome) or with a rare tumor commonly found in the context of germline predisposition (e.g., rhabdoid tumor predisposition …

Accelerated Somatic Mutation Calling For Whole-Genome And Whole-Exome Sequencing Data From Heterogenous Tumor Samples, Shuangxi Ji, Tong Zhu, Ankit Sethia, Wenyi Wang

Faculty, Staff and Student Publications

Accurate detection of somatic mutations in DNA sequencing data is a fundamental prerequisite for cancer research. Previous analytical challenges were overcome by consensus mutation calling from four to five popular callers. This, however, increases the already nontrivial computing time from individual callers. Here, we launch MuSE 2, powered by multistep parallelization and efficient memory allocation, to resolve the computing time bottleneck. MuSE 2 speeds up 50 times more than MuSE 1 and eight to 80 times more than other popular callers. Our benchmark study suggests combining MuSE 2 and the recently accelerated Strelka2 achieves high efficiency and accuracy in analyzing …

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 …

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, Christine Ambrosone, Dezheng Huo, Stefan Ambs, 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.

Quorum-Sensing Agr System Of Staphylococcus Aureus Primes Gene Expression For Protection From Lethal Oxidative Stress, Magdalena Podkowik, Andrew I Perault, Gregory Putzel, Andrew Pountain, Jisun Kim, Ashley L Dumont, Erin E Zwack, Robert J Ulrich, Theodora K Karagounis, Chunyi Zhou, Andreas F Haag, Julia Shenderovich, Gregory A Wasserman, Junbeom Kwon, John Chen, Anthony R Richardson, Jeffrey N Weiser, Carla R Nowosad, Desmond S Lun, Dane Parker, Alejandro Pironti, Xilin Zhao, Karl Drlica, Itai Yanai, Victor J Torres, Bo Shopsin

Faculty, Staff and Student Publications

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic …

Evolution Of Chromosome-Arm Aberrations In Breast Cancer Through Genetic Network Rewiring, Elena Kuzmin, Toby M Baker, Tom Lesluyes, Jean Monlong, Kento T Abe, Paula P Coelho, Michael Schwartz, Joseph Del Corpo, Dongmei Zou, Genevieve Morin, Alain Pacis, Yang Yang, Constanza Martinez, Jarrett Barber, Hellen Kuasne, Rui Li, Mathieu Bourgey, Anne-Marie Fortier, Peter G Davison, Atilla Omeroglu, Marie-Christine Guiot, Quaid Morris, Claudia L Kleinman, Sidong Huang, Anne-Claude Gingras, Jiannis Ragoussis, Guillaume Bourque, Peter Van Loo, Morag Park

Faculty, Staff and Student Publications

The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. Analysis of The Cancer Genome Atlas data shows recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a panel of 23 primary tumor/patient-derived xenograft basal breast cancers reveals early evolution of chr4p deletion. Mechanistically we show that chr4p loss is associated with enhanced proliferation. Gene function studies identify an unknown gene, C4orf19, within chr4p, which suppresses proliferation when overexpressed-a member of the PDCD10-GCKIII kinase module …

Fourteen-Day Vonoprazan-Based Bismuth Quadruple Therapy For H Pylori Eradication In An Area With High Clarithromycin And Levofloxacin Resistance: A Prospective Randomized Study (Vq-Hp Trial), Nuttapat Tungtrongchitr, Phubordee Bongkotvirawan, Sarita Ratana-Amornpin, Sith Siramolpiwat, Thanee Eiamsitrakoon, Pornpen Gamnarai, Arti Wongcha-Um, Yoshio Yamaoka, Kammal Kumar Pawa, Ratha-Korn Vilaichone

Faculty, Staff and Students Publications

Potassium-competitive acid blockers (P-CABs) provide potent acid inhibition, yet studies on P-CAB-based quadruple therapy for H. pylori eradication are limited. We theorized that integrating bismuth subsalicylate into a quadruple therapy regimen could enhance eradication rates. However, data on the efficacy of vonoprazan bismuth quadruple therapy are notably scarce. Therefore, the aim of this study was to evaluate the efficacy of vonoprazan-based bismuth quadruple therapy in areas with high clarithromycin and levofloxacin resistance. This was a prospective, single-center, randomized trial conducted to compare the efficacy of 7-day and 14-day vonoprazan-based bismuth quadruple therapy for H. pylori eradication between June 1, 2021, …

Germline Structural Variation Globally Impacts The Cancer Transcriptome Including Disease-Relevant Genes, Fengju Chen, Yiqun Zhang, Fritz J Sedlazeck, Chad J Creighton

Faculty, Staff and Students Publications

Germline variation and somatic alterations contribute to the molecular profile of cancers. We combine RNA with whole genome sequencing across 1,218 cancer patients to determine the extent germline structural variants (SVs) impact expression of nearby genes. For hundreds of genes, recurrent and common germline SV breakpoints within 100 kb associate with increased or decreased expression in tumors spanning various tissues of origin. A significant fraction of germline SV expression associations involves duplication of intergenic enhancers or 3' UTR disruption. Genes altered by both somatic and germline SVs include ATRX and CEBPA. Genes essential in cancer cell lines include BARD1 and …

Grb2 Stabilizes Rad51 At Reversed Replication Forks Suppressing Genomic Instability And Innate Immunity Against Cancer, Zu Ye, Shengfeng Xu, Yin Shi, Xueqian Cheng, Yuan Zhang, Sunetra Roy, Sarita Namjoshi, Michael A Longo, Todd M Link, Katharina Schlacher, Guang Peng, Dihua Yu, Bin Wang, John A Tainer, Zamal Ahmed

Faculty, Staff and Student Publications

Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS-STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment …

Feasibility And Clinical Utility Of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified In Research Germline Sequencing: A Prospective Interventional Study, Megan L. Hutchcraft, Shulin Zhang, Nan Lin, Justine C. Pickarski, Elizabeth Belcher, Sainan Wei, Therese J. Bocklage, Rachel W. Miller, John L. Villano, Michael J. Cavnar, Joseph Kim, Susanne M. Arnold, Frederick R. Ueland, Jill M. Kolesar

Markey Cancer Center Faculty Publications

PURPOSE

Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant sec- ondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician.

METHODS

This prospective, interventional cohort study enrolled Total Cancer Care par- ticipants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic anal- ysis in a Clinical Laboratory Improvement Amendments–certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College …

Evaluation Of The Cellular And Physiologic Impact Of Mitomycin C On Colon Cancer, Hannah Mcdonald

Theses and Dissertations--Clinical and Translational Science

Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) with Mitomycin C (MMC) has more than doubled the overall and disease-free survival in patients with peritoneal metastases (PM) due to colorectal cancer (CRC) over the past two decades. Although MMC is the most used HIPEC drug for PM due to CRC, dosing protocols vary dramatically between and within institutions across the world. Additionally, little is known about the impact of hyperthermia and MMC on intracellular pathways for CRC. The aim of this work is to determine the optimal dosing strategy in the clinical application of MMC and hyperthermia for treatment of …

Developing Medical Genetics In A Low-Income Country: Unveiling The Journey Of The Pakistani Society Of Medical Genetics And Genomics (Psmg), Aisha Furqan, Syed A Ahmed, Rizwan Naeem, Myla Ashfaq

Faculty, Staff and Student Publications

No abstract provided.

Multiple Unfolded Protein Response Pathways Cooperate To Link Cytosolic Dsdna Release To Stimulator Of Interferon Gene Activation, Tiancheng Hu, Yiping Liu, Jeremy Fleck, Cason King, Elaine Schalk, Zhenyu Zhang, Andrew Mehle, Judith A Smith

Faculty, Staff and Student Publications

The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal DNA or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought to determine if ER stress generated a STING ligand, and to identify the UPR pathways involved. Induction of IFN-β expression following stimulation with the UPR inducer thapsigargin (TPG) or oxygen glucose deprivation required both STING and the dsDNA-sensing cyclic GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, and immunofluorescence visualized dsDNA punctae in …

Genetic Inactivation Of Β-Catenin Is Salubrious, Whereas Its Activation Is Deleterious In Desmoplakin Cardiomyopathy, Melis Olcum, Siyang Fan, Leila Rouhi, Sirisha Cheedipudi, Benjamin Cathcart, Hyun-Hwan Jeong, Zhongming Zhao, Priyatansh Gurha, Ali J Marian

Faculty, Staff and Student Publications

AIMS: Mutations in the DSP gene encoding desmoplakin, a constituent of the desmosomes at the intercalated discs (IDs), cause a phenotype that spans arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy. It is typically characterized by biventricular enlargement and dysfunction, myocardial fibrosis, cell death, and arrhythmias. The canonical wingless-related integration (cWNT)/β-catenin pathway is implicated in the pathogenesis of ACM. The β-catenin is an indispensable co-transcriptional regulator of the cWNT pathway and a member of the IDs. We genetically inactivated or activated β-catenin to determine its role in the pathogenesis of desmoplakin cardiomyopathy.

METHODS AND RESULTS: The Dsp gene was conditionally deleted in …