Genetic Phenomena Commons^™

Gut Bacterial Isoamylamine Promotes Age-Related Cognitive Dysfunction By Promoting Microglial Cell Death, Yun Teng, Jingyao Mu, Fangyi Xu, Xiangcheng Zhang, Mukesh K Sriwastva, Qiaohong M Liu, Xiaohong Li, Chao Lei, Kumaran Sundaram, Xin Hu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Eric C Rouchka, Xiang Zhang, Jun Yan, Michael L Merchant, Huang-Ge Zhang

Faculty, Staff and Student Publications

The intestinal microbiome releases a plethora of small molecules. Here, we show that the Ruminococcaceae metabolite isoamylamine (IAA) is enriched in aged mice and elderly people, whereas Ruminococcaceae phages, belonging to the Myoviridae family, are reduced. Young mice orally administered IAA show cognitive decline, whereas Myoviridae phage administration reduces IAA levels. Mechanistically, IAA promotes apoptosis of microglial cells by recruiting the transcriptional regulator p53 to the S100A8 promoter region. Specifically, IAA recognizes and binds the S100A8 promoter region to facilitate the unwinding of its self-complementary hairpin structure, thereby subsequently enabling p53 to access the S100A8 promoter and enhance S100A8 expression. …

High-Sensitivity Next-Generation Sequencing Mrd Assessment In All Identifies Patients At Very Low Risk Of Relapse, Nicholas J Short, Hagop Kantarjian, Farhad Ravandi, Marina Konopleva, Nitin Jain, Rashmi Kanagal-Shamanna, Keyur P Patel, Walid Macaron, Tapan M Kadia, Sa Wang, Jeffrey L Jorgensen, Joseph D Khoury, Musa Yilmaz, Partow Kebriaei, Koichi Takahashi, Guillermo Garcia-Manero, Naval Daver, Sean M Post, Xuelin Huang, Steven M Kornblau, Sara Pelletier, Wilmer Flores, Jairo Matthews, Rebecca Garris, Elias Jabbour

Faculty, Staff and Student Publications

Measurable residual disease (MRD) is highly prognostic for relapse and overall survival (OS) in acute lymphoblastic leukemia (ALL), although many patients with apparent "MRD negativity" by standard assays still relapse. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay in 74 adults with ALL undergoing frontline therapy. Among remission samples that were MRD negative by multiparameter flow cytometry (MFC), 46% were MRD+ by the NGS assay. After 1 cycle of induction chemotherapy, MRD negativity by MFC at a sensitivity of 1 × 10-4 and NGS at a sensitivity of 1 × 10-6 was achieved in …

Treatment-Free Remission After Ceasing Venetoclax-Based Therapy In Patients With Acute Myeloid Leukemia, Chong Chyn Chua, Danielle Hammond, Andrew Kent, Ing Soo Tiong, Marina Y Konopleva, Daniel A Pollyea, Courtney D Dinardo, Andrew H Wei

Faculty, Staff and Student Publications

The clinical benefit of adding venetoclax (VEN) to hypomethylating agents or low-dose cytarabine in older and/or unfit patients with newly diagnosed acute myeloid leukemia (AML) has been confirmed in phase 3 studies. With the increased uptake of VEN-based therapies for patients with AML, a pertinent question is whether treatment can be safely ceased among patients who have achieved sustained remission. We hypothesized that a proportion of patients opting to cease therapy may benefit from a treatment-free remission (TFR) period without indefinite treatment. We report the retrospective outcomes of 29 patients in remission for a minimum of 12 months on VEN-based …

Metabolic Requirement For Got2 In Pancreatic Cancer Depends On Environmental Context, Samuel A Kerk, Lin Lin, Amy L Myers, Damien J Sutton, Anthony Andren, Peter Sajjakulnukit, Li Zhang, Yaqing Zhang, Jennifer A Jiménez, Barbara S Nelson, Brandon Chen, Anthony Robinson, Galloway Thurston, Samantha B Kemp, Nina G Steele, Megan T Hoffman, Hui-Ju Wen, Daniel Long, Sarah E Ackenhusen, Johanna Ramos, Xiaohua Gao, Zeribe C Nwosu, Stefanie Galban, Christopher J Halbrook, David B Lombard, David R Piwnica-Worms, Haoqiang Ying, Marina Pasca Di Magliano, Howard C Crawford, Yatrik M Shah, Costas A Lyssiotis

Faculty, Staff and Student Publications

Mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2) is part of the malate-aspartate shuttle, a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and α-ketoglutarate (αKG) production, stalled glycolysis, disrupted the TCA cycle, and impaired proliferation. Oxidizing NADH through chemical or genetic means resolved the redox imbalance …

Immunophenotypic And Molecular Features Of Acute Myeloid Leukemia With Plasmacytoid Dendritic Cell Differentiation Are Distinct From Blastic Plasmacytoid Dendritic Cell Neoplasm, Wei Wang, Jie Xu, Joseph D Khoury, Naveen Pemmaraju, Hong Fang, Roberto N Miranda, C Cameron Yin, Siba El Hussein, Fuli Jia, Zhenya Tang, Shimin Hu, Marina Konopleva, L Jeffrey Medeiros, Sa A Wang

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) with ≥2% plasmacytoid dendritic cells (pDC) has been recently described as AML with pDC differentiation (pDC-AML) characterized by pDC expansion with frequent RUNX1 mutations. In this study, we investigated a cohort of 53 pDC-AML cases representing about 3% of all AML cases. We characterized their immunophenotype and genetic profiles and compared these findings with blastic plasmacytoid dendritic cell neoplasm (BPDCN). pDC-differentiation/expansion was preferentially observed in AML with an immature myeloid or myelomonocytic immunophenotype, where myeloblasts were frequently positive for CD34 (98%), CD117 (94%), HLA-DR (100%) and TdT (79%), with increased CD123 (89%) expression. The median number …

Multi-Modal Molecular Programs Regulate Melanoma Cell State, Miles C Andrews, Junna Oba, Chang-Jiun Wu, Haifeng Zhu, Tatiana Karpinets, Caitlin A Creasy, Marie-Andrée Forget, Xiaoxing Yu, Xingzhi Song, Xizeng Mao, A Gordon Robertson, Gabriele Romano, Peng Li, Elizabeth M Burton, Yiling Lu, Robert Szczepaniak Sloane, Khalida M Wani, Kunal Rai, Alexander J Lazar, Lauren E Haydu, Matias A Bustos, Jianjun Shen, Yueping Chen, Margaret B Morgan, Jennifer A Wargo, Lawrence N Kwong, Cara L Haymaker, Elizabeth A Grimm, Patrick Hwu, Dave S B Hoon, Jianhua Zhang, Jeffrey E Gershenwald, Michael A Davies, P Andrew Futreal, Chantale Bernatchez, Scott E Woodman

Faculty, Staff and Student Publications

Melanoma cells display distinct intrinsic phenotypic states. Here, we seek to characterize the molecular regulation of these states using multi-omic analyses of whole exome, transcriptome, microRNA, long non-coding RNA and DNA methylation data together with reverse-phase protein array data on a panel of 68 highly annotated early passage melanoma cell lines. We demonstrate that clearly defined cancer cell intrinsic transcriptomic programs are maintained in melanoma cells ex vivo and remain highly conserved within melanoma tumors, are associated with distinct immune features within tumors, and differentially correlate with checkpoint inhibitor and adoptive T cell therapy efficacy. Through integrative analyses we demonstrate …

Tp53 Copy Number And Protein Expression Inform Mutation Status Across Risk Categories In Acute Myeloid Leukemia, Mehrnoosh Tashakori, Tapan Kadia, Sanam Loghavi, Naval Daver, Rashmi Kanagal-Shamanna, Sherry Pierce, Dawen Sui, Peng Wei, Farnoosh Khodakarami, Zhenya Tang, Mark Routbort, Carol A Bivins, Elias J Jabbour, L Jeffrey Medeiros, Kapil Bhalla, Hagop M Kantarjian, Farhad Ravandi, Joseph D Khoury

Faculty, Staff and Student Publications

Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as …

Dissecting The Treatment-Naive Ecosystem Of Human Melanoma Brain Metastasis, Jana Biermann, Johannes C Melms, Amit Dipak Amin, Yiping Wang, Lindsay A Caprio, Alcida Karz, Somnath Tagore, Irving Barrera, Miguel A Ibarra-Arellano, Massimo Andreatta, Benjamin T Fullerton, Kristjan H Gretarsson, Varun Sahu, Vaibhav S Mangipudy, Trang T T Nguyen, Ajay Nair, Meri Rogava, Patricia Ho, Peter D Koch, Matei Banu, Nelson Humala, Aayushi Mahajan, Zachary H Walsh, Shivem B Shah, Daniel H Vaccaro, Blake Caldwell, Michael Mu, Florian Wünnemann, Margot Chazotte, Simon Berhe, Adrienne M Luoma, Joseph Driver, Matthew Ingham, Shaheer A Khan, Suthee Rapisuwon, Craig L Slingluff, Thomas Eigentler, Martin Röcken, Richard Carvajal, Michael B Atkins, Michael A Davies, Albert Agustinus, Samuel F Bakhoum, Elham Azizi, Markus Siegelin, Chao Lu, Santiago J Carmona, Hanina Hibshoosh, Antoni Ribas, Peter Canoll, Jeffrey N Bruce, Wenya Linda Bi, Praveen Agrawal, Denis Schapiro, Eva Hernando, Evan Z Macosko, Fei Chen, Gary K Schwartz, Benjamin Izar

Faculty, Staff and Student Publications

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant …

Drug-Target Network Study Reveals The Core Target-Protein Interactions Of Various Covid-19 Treatments, Yulin Dai, Hui Yu, Qiheng Yan, Bingrui Li, Andi Liu, Wendao Liu, Xiaoqian Jiang, Yejin Kim, Yan Guo, Zhongming Zhao

Faculty, Staff and Student Publications

The coronavirus disease 2019 (COVID-19) pandemic has caused a dramatic loss of human life and devastated the worldwide economy. Numerous efforts have been made to mitigate COVID-19 symptoms and reduce the death rate. We conducted literature mining of more than 250 thousand published works and curated the 174 most widely used COVID-19 medications. Overlaid with the human protein-protein interaction (PPI) network, we used Steiner tree analysis to extract a core subnetwork that grew from the pharmacological targets of ten credible drugs ascertained by the CTD database. The resultant core subnetwork consisted of 34 interconnected genes, which were associated with 36 …

Vitamin E Enhances Cancer Immunotherapy By Reinvigorating Dendritic Cells Via Targeting Checkpoint Shp1, Xiangliang Yuan, Yimin Duan, Yi Xiao, Kai Sun, Yutao Qi, Yuan Zhang, Zamal Ahmed, Davide Moiani, Jun Yao, Hongzhong Li, Lin Zhang, Arseniy E Yuzhalin, Ping Li, Chenyu Zhang, Akosua Badu-Nkansah, Yohei Saito, Xianghua Liu, Wen-Ling Kuo, Haoqiang Ying, Shao-Cong Sun, Jenny C Chang, John A Tainer, Dihua Yu

Faculty, Staff and Student Publications

Despite the popular use of dietary supplements during conventional cancer treatments, their impacts on the efficacies of prevalent immunotherapies, including immune-checkpoint therapy (ICT), are unknown. Surprisingly, our analyses of electronic health records revealed that ICT-treated patients with cancer who took vitamin E (VitE) had significantly improved survival. In mouse models, VitE increased ICT antitumor efficacy, which depended on dendritic cells (DC). VitE entered DCs via the SCARB1 receptor and restored tumor-associated DC functionality by directly binding to and inhibiting protein tyrosine phosphatase SHP1, a DC-intrinsic checkpoint. SHP1 inhibition, genetically or by VitE treatment, enhanced tumor antigen cross-presentation by DCs and …

Synthetic Essentiality Of Tryptophan 2,3-Dioxygenase 2 In Apc-Mutated Colorectal Cancer, Rumi Lee, Jiexi Li, Jun Li, Chang-Jiun Wu, Shan Jiang, Wen-Hao Hsu, Deepavali Chakravarti, Peiwen Chen, Kyle A Labella, Jing Li, Denise J Spring, Di Zhao, Y Alan Wang, Ronald A Depinho

Faculty, Staff and Student Publications

Inactivation of adenomatous polyposis coli (APC) is common across many cancer types and serves as a critical initiating event in most sporadic colorectal cancers. APC deficiency activates WNT signaling, which remains an elusive target for cancer therapy, prompting us to apply the synthetic essentiality framework to identify druggable vulnerabilities for APC-deficient cancers. Tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient colorectal cancer. Mechanistically, APC deficiency results in the TCF4/β-catenin-mediated upregulation of TDO2 gene transcription. TDO2 in turn activates the Kyn-AhR pathway, which increases glycolysis to drive anabolic cancer cell growth and CXCL5 secretion to recruit …

Webcsea: Web-Based Cell-Type-Specific Enrichment Analysis Of Genes, Yulin Dai, Ruifeng Hu, Andi Liu, Kyung Serk Cho, Astrid Marilyn Manuel, Xiaoyang Li, Xianjun Dong, Peilin Jia, Zhongming Zhao

Faculty, Staff and Student Publications

Human complex traits and common diseases show tissue- and cell-type- specificity. Recently, single-cell RNA sequencing (scRNA-seq) technology has successfully depicted cellular heterogeneity in human tissue, providing an unprecedented opportunity to understand the context-specific expression of complex trait-associated genes in human tissue-cell types (TCs). Here, we present the first web-based application to quickly assess the cell-type-specificity of genes, named Web-based Cell-type Specific Enrichment Analysis of Genes (WebCSEA, available at https://bioinfo.uth.edu/webcsea/). Specifically, we curated a total of 111 scRNA-seq panels of human tissues and 1,355 TCs from 61 different general tissues across 11 human organ systems. We adapted our previous decoding tissue-specificity …

Modeling The Prognostic Impact Of Circulating Tumor Cells Enumeration In Metastatic Breast Cancer For Clinical Trial Design Simulation, Lorenzo Gerratana, Jean-Yves Pierga, James M Reuben, Andrew A Davis, Firas H Wehbe, Luc Dirix, Tanja Fehm, Franco Nolé, Rafael Gisbert-Criado, Dimitrios Mavroudis, Salvatore Grisanti, Jose A Garcia-Saenz, Justin Stebbing, Carlos Caldas, Paola Gazzaniga, Luis Manso, Rita Zamarchi, Marta Bonotto, Angela Fernandez De Lascoiti, Leticia De Mattos-Arruda, Michail Ignatiadis, Maria-Teresa Sandri, Daniele Generali, Carmine De Angelis, Sarah-Jane Dawson, Wolfgang Janni, Vicente Carañana, Sabine Riethdorf, Erich-Franz Solomayer, Fabio Puglisi, Mario Giuliano, Klaus Pantel, François-Clément Bidard, Massimo Cristofanilli

Faculty, Staff and Student Publications

Despite the strong prognostic stratification of circulating tumor cells (CTCs) enumeration in metastatic breast cancer (MBC), current clinical trials usually do not include a baseline CTCs in their design. This study aimed to generate a classifier for CTCs prognostic simulation in existing datasets for hypothesis generation in patients with MBC. A K-nearest neighbor machine learning algorithm was trained on a pooled dataset comprising 2436 individual MBC patients from the European Pooled Analysis Consortium and the MD Anderson Cancer Center to identify patients likely to have CTCs ≥ 5/7 mL blood (StageIVaggressive vs StageIVindolent). The model had a 65.1% accuracy and …

Bloodstream Infections In Hematologic Malignancy Patients With Fever And Neutropenia: Are Empirical Antibiotic Therapies In The United States Still Effective?, Andrea J Zimmer, Erica Stohs, Jane Meza, Christopher Arnold, John W Baddley, Pranatharthi Chandrasekar, Zeinab El Boghdadly, Carlos A Gomez, Eileen K Maziarz, Jose G Montoya, Steven Pergam, Kenneth V Rolston, Michael J Satlin, Gowri Satyanarayana, Shmuel Shoham, Lynne Strasfeld, Randy Taplitz, Thomas J Walsh, Jo-Anne H Young, Yuning Zhang, Alison G Freifeld

Faculty, Staff and Student Publications

Background: Rising antimicrobial resistance rates may impact the efficacy of empirical antibiotic treatment for febrile neutropenia in high-risk cancer patients. Lacking contemporary data about the epidemiology, antibiotic resistance patterns, and clinical outcomes from bloodstream infections (BSIs) in US cancer patients, it is unclear if current guidelines remain relevant.

Methods: In a cross-sectional study, 14 US cancer centers prospectively identified BSIs in high-risk febrile neutropenic (FN) patients, including those receiving chemotherapy for hematologic malignancies or hematopoietic stem cell transplantation.

Results: Among 389 organisms causing BSI in 343 patients, there was an equal distribution of gram-negative (GN) and gram-positive (GP) bacteria, with …

A Win Consortium Phase I Study Exploring Avelumab, Palbociclib, And Axitinib In Advanced Non-Small Cell Lung Cancer, Benjamin Solomon, Ana Callejo, Jair Bar, Guy Berchem, Lyudmila Bazhenova, Pierre Saintigny, Fanny Wunder, Jacques Raynaud, Nicolas Girard, J Jack Lee, Raed Sulaiman, Bruce Prouse, Catherine Bresson, Hila Ventura, Shai Magidi, Eitan Rubin, Brandon Young, Amir Onn, Brian Leyland-Jones, Richard L Schilsky, Vladimir Lazar, Enriqueta Felip, Razelle Kurzrock

Faculty, Staff and Student Publications

Background: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC).

Methods: Patients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD-L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design).

Results: Fifteen patients were treated (five centers, four countries): six at each of dose levels 1 (DL1) and DL2; three at DL3. …

Frailty Repels The Knife: The Impact Of Frailty Index On Surgical Intervention And Outcomes, Katelyn F Handley, Anil K Sood, Graziela Zibetti Dal Molin, Shannon N Westin, Larissa A Meyer, Bryan Fellman, Pamela T Soliman, Robert L Coleman, Nicole D Fleming

Faculty, Staff and Student Publications

Objective: To assess the impact of frailty in patients with ovarian cancer on surgical procedures and outcomes.

Methods: A retrospective review of patients with stage II-IV ovarian cancer from April 2013 to September 2017 was performed. Patients were triaged by laparoscopy to determine primary resectability. The adjusted modified frailty index score (amFI) was calculated and amFI ≥2 classified as high frailty. Clinical outcomes, progression free survival (PFS) and overall survival (OS) were estimated.

Results: 592 patients met inclusion criteria; amFI of 0, 1 and ≥ 2 was noted in 57%, 29%, and 14%, respectively. Patients with high frailty were less …

Hap40 Is A Conserved Central Regulator Of Huntingtin And A Potential Modulator Of Huntington’S Disease Pathogenesis, Shiyu Xu, Gang Li, Xin Ye, Dongsheng Chen, Zhihua Chen, Zhen Xu, Moretti Daniele, Sara Tambone, Alessandra Ceccacci, Licia Tomei, Lili Ye, Yue Yu, Amanda Solbach, Stephen M Farmer, Erin Furr Stimming, George Mcallister, Deanna M Marchionini, Sheng Zhang

Faculty, Staff and Student Publications

Perturbation of huntingtin (HTT)'s physiological function is one postulated pathogenic factor in Huntington's disease (HD). However, little is known how HTT is regulated in vivo. In a proteomic study, we isolated a novel ~40kDa protein as a strong binding partner of Drosophila HTT and demonstrated it was the functional ortholog of HAP40, an HTT associated protein shown recently to modulate HTT's conformation but with unclear physiological and pathologic roles. We showed that in both flies and human cells, HAP40 maintained conserved physical and functional interactions with HTT. Additionally, loss of HAP40 resulted in similar phenotypes as HTT knockout. More strikingly, …

Prospecting Cellular Gold Nanoparticle Biomineralization As A Viable Alternative To Prefabricated Gold Nanoparticles, Aaron S Schwartz-Duval, Konstantin V Sokolov

Faculty, Staff and Student Publications

Gold nanoparticles (GNPs) have shown considerable potential in a vast number of biomedical applications. However, currently there are no clinically approved injectable GNP formulations. Conversely, gold salts have been used in the clinic for nearly a century. Further, there is evidence of GNP formation in patients treated with gold salts (i.e., chrysiasis). Recent reports evaluating this phenomenon in human cells and in murine models indicate that the use of gold ions for in situ formation of theranostic GNPs could greatly improve the delivery within dense biological tissues, increase efficiency of intracellular gold uptake, and specificity of GNP formation within cancer …

Functional Genomic Analysis Of Epithelioid Sarcoma Reveals Distinct Proximal And Distal Subtype Biology, Samuel V Rasmussen, Jia Xiang Jin, Lissett R Bickford, Andrew D Woods, Felix Sahm, Kenneth A Crawford, Kiyo Nagamori, Hiroaki Goto, Keila E Torres, Angelo Sidoni, Erin R Rudzinski, Khin Thway, Robin L Jones, Alessio Ciulli, Hollis Wright, Melvin Lathara, Ganapati Srinivasa, Kavya Kannan, Paul H Huang, Thomas G P Grünewald, Noah E Berlow, Charles Keller

Faculty, Staff and Student Publications

Background: Metastatic epithelioid sarcoma (EPS) remains a largely unmet clinical need in children, adolescents and young adults despite the advent of EZH2 inhibitor tazemetostat.

Methods: In order to realise consistently effective drug therapies, a functional genomics approach was used to identify key signalling pathway vulnerabilities in a spectrum of EPS patient samples. EPS biopsies/surgical resections and cell lines were studied by next-generation DNA exome and RNA deep sequencing, then EPS cell cultures were tested against a panel of chemical probes to discover signalling pathway targets with the most significant contributions to EPS tumour cell maintenance.

Results: Other biologically inspired functional …

Leveraging Single-Cell Sequencing To Unravel Intratumour Heterogeneity And Tumour Evolution In Human Cancers, Amy L Bowes, Maxime Tarabichi, Nischalan Pillay, Peter Van Loo

Faculty, Staff and Student Publications

Intratumour heterogeneity (ITH) and tumour evolution are well-documented phenomena in human cancers. While the advent of next-generation sequencing technologies has facilitated the large-scale capture of genomic data, the field of single-cell genomics is nascent but rapidly advancing and generating many new insights into the complex molecular mechanisms of tumour biology. In this review, we provide an overview of current single-cell DNA sequencing technologies, exploring how recent methodological advancements have enumerated new insights into ITH and tumour evolution. Areas highlighted include the potential power of single-cell genome sequencing studies to explore evolutionary dynamics contributing to tumourigenesis through to progression, metastasis, and …