BREAKING INSIGHTS 2612 Genome-Wide DNA Methylation Profiling of Esophageal Squamous Cell Carcinoma from Global High-Incidence Regions Identifies Crucial Genes and Potential Cancer Highlights from Recent Cancer Literature 2575 Markers A C Fazlur Rahman Talukdar, Sheila C. Soares Lima, REVIEW Rita Khoueiry, Ruhina Shirin Laskar, Cyrille Cuenin, Bruna Pereira Sorroche, Anne-Claire Boisson, 2577 (Oligo)metastasis as a Spectrum of Disease Behnoush Abedi-Ardekani, Christine Carreira, Stanley I. Gutiontov, Sean P. Pitroda, Phuoc T. Tran, and Diana Menya, Charles P. Dzamalala, Mathewos Assefa, Ralph R. Weichselbaum Abraham Aseffa, Vera Miranda-Goncalves,¸ Carmen Jerónimo, Rui M. Henrique, Ramin Shakeri, Reza Malekzadeh, Nagla Gasmelseed, Mona Ellaithi, CANCER RESEARCH HIGHLIGHTS Nitin Gangane, Daniel R.S. Middleton, – Florence Le Calvez-Kelm, Akram Ghantous, 2584 Acute Kidney Injury Induced Systemic Inflammation € and Risk of Kidney Cancer Formation Maria Leon Roux, Joachim Schuz, Valerie McCormack, Sergei Kusmartsev M. Iqbal Parker, Luis Felipe Ribeiro Pinto, and Zdenko Herceg See related article, p. 2690 This largest genome-wide DNA methylation study on ESCC from high-incidence populations of the world 2586 The Panorama of Cancer Genetics identifies functionally relevant and robust DNAme Joel S. Bader events that could serve as potential tumor-specific See related article, p. 2588 markers.

GENOME AND EPIGENOME METABOLISM AND CHEMICAL BIOLOGY

2588 The Landscape of the Heritable Cancer Genome 2625 Mevalonate Pathway Inhibition Slows Breast Cancer Metastasis via Reduced N-glycosylation Abundance and Viola Fanfani, Luca Citi, Adrian L. Harris, Branching Francesco Pezzella, and Giovanni Stracquadanio Rosemary Yu, Joseph Longo, Jenna E. van Leeuwen, This study describes a new statistical method to identify Cunjie Zhang, Emily Branchard, Mohamad Elbaz, genes associated with cancer heritability in the broader David W. Cescon, Richard R. Drake, James W. Dennis, population, creating a map of the heritable cancer genome with gene-level resolution. and Linda Z. Penn These findings show that metastatic breast cancer cells See related commentary, p. 2586 depend on the fluvastatin-sensitive mevalonate pathway to support protein N-glycosylation, warranting immediate 2600 Single-Cell RNA Sequencing Reveals the Cellular Origin clinical testing of fluvastatin as an adjuvant therapy for breast and Evolution of Breast Cancer in BRCA1 Mutation cancer. Carriers Li Hu, Liming Su, Hainan Cheng, Chunling Mo, Tao Ouyang, Jinfeng Li, Tianfeng Wang, Zhaoqing Fan, Tie Fan, Benyao Lin, Jianguang Zhang, and Yuntao Xie Single-cell RNA-seq data indicate that basal-like breast cancer (ERneg) might originate from luminal progenitors, and ERhigh luminal breast cancer might originate from mature luminal cells in BRCA1 mutation carriers.

MOLECULAR CELL BIOLOGY TUMOR BIOLOGY AND IMMUNOLOGY

2636 MYC-Activated LncRNA MNX1-AS1 Promotes the 2690 Acute Kidney Injury Instigates Malignant Renal Cell Progression of Colorectal Cancer by Stabilizing YB1 Carcinoma via CXCR2 in Mice with Inactivated Trp53 and Qi-Nian Wu, Xiao-Jing Luo, Jia Liu, Yun-Xin Lu, Pten in Proximal Tubular Kidney Epithelial Cells Yun Wang, Jingjing Qi, Ze-Xian Liu, Qi-Tao Huang, Xunian Zhou, Fei Xiao, Hikaru Sugimoto, Bingrui Li, Ze-Kun Liu, Jia-Bin Lu, Ying Jin, Heng-Ying Pu, Kathleen M. McAndrews, and Raghu Kalluri Pei-Shan Hu, Jia-Bo Zheng, Zhao-Lei Zeng, These results identify a role for CXCL1/CXCR2 and the tumor Huai-Qiang Ju, Dan Xie, Qi Zhao, and Ruihua Xu microenvironment in the development of RCC. This study highlights the discovery of a novel colorectal See related commentary, p. 2584 cancer biomarker and therapeutic target MNX1-AS1, a long noncoding RNA that drives proliferation via a 2703 POT1 Regulates Proliferation and Confers Sexual MYC/MNX1-AS1/YB1 signaling pathway. Dimorphism in Glioma Ali Jalali, Kwanha Yu, Vivek Beechar, 2651 YTHDF1 Promotes Gastric Carcinogenesis by Navish A. Bosquez Huerta, Anthony Grichuk, Controlling Translation of FZD7 Deepika Mehra, Brittney Lozzi, Kathleen Kong, A C Jingnan Pi, Wen Wang, Ming Ji, Xiaoshuang Wang, Kenneth L. Scott, Ganesh Rao, Matthew N. Bainbridge, Xueju Wei, Jing Jin, Tao Liu, Jiaqi Qiang, Zhihong Qi, Melissa L. Bondy, and Benjamin Deneen Feng Li, Yue Liu, Yanni Ma, Yanmin Si, Yue Huo, This study shows that manipulation of POT1 expression in Yufeng Gao, Yiying Chen, Lei Dong, Rui Su, glioma has sex-specific effects on tumorigenesis and Jianjun Chen, Shuan Rao, Ping Yi, Shuyang Yu, associated immune signatures. Fang Wang, and Jia Yu This study provides a rationale for controlling translation of 2714 MEK Inhibition Remodels the Immune Landscape of key oncogenic drivers in cancer by manipulating epigenetic Mutant KRAS Tumors to Overcome Resistance to PARP regulators, representing a novel and efficient strategy for and Immune Checkpoint Inhibitors anticancer treatment. Bin Yang, Xi Li, Yu Fu, Ensong Guo, Youqiong Ye, Fuxia Li, Si Liu, Rourou Xiao, Chen Liu, Funian Lu, a 2666 CDK2-Mediated Upregulation of TNF as a Mechanism Jia Huang, Tianyu Qin, Leng Han, Guang Peng, of Selective Cytotoxicity in Acute Leukemia Gordon B. Mills, Chaoyang Sun, and Gang Chen Husheng Ding, Nicole D. Vincelette, This study provides key insights into the potential for using Cordelia D. McGehee, Mira A. Kohorst, Brian D. Koh, MEKi combined with PARPi and anti-PD-L1 for the treatment Annapoorna Venkatachalam, X. Wei Meng, of all mutant KRAS tumors. Paula A. Schneider, Karen S. Flatten, Kevin L. Peterson, Cristina Correia, Sun-Hee Lee, Mrinal Patnaik, 2730 Deciphering the Role of Intestinal Crypt Cell Jonathan A. Webster, Gabriel Ghiaur, B. Douglas Smith, Populations in Resistance to Chemotherapy Judith E. Karp, Keith W. Pratz, Hu Li, Larry M. Karnitz, Carla Frau, Catherine Jamard, Gaspard Delpouve, and Scott H. Kaufmann Gabriela D.A. Guardia, Christelle Machon, Camilla Pilati, This study demonstrates that replication checkpoint Clementine Le Neve, Pierre Laurent-Puig, inhibitors can kill AML cells through a pathway involving Jerôme Guitton, Pedro A.F. Galante, Luiz O. Penalva, AP1-mediated TNF gene activation and subsequent Jean-Noel Freund, Christelle de la Fouchardiere, and TP53-independent, TNFa-induced apoptosis, which can Michelina Plateroti potentially be exploited clinically. This study unveils paradoxical roles for MSI1, underlining its importance in facilitating intestinal regeneration upon injury 2679 Dynamic Regulation of Expression of KRAS and Its but also unraveling its new function in drug-resistant Effectors Determines the Ability to Initiate Tumorigenesis in Pancreatic Acinar Cells colorectal cancer stem cells. Mohamad Assi, Younes Achouri, Axelle Loriot, 2745 Porphyromonas gingivalis Promotes Colorectal Nicolas Dauguet, Hajar Dahou, Jonathan Baldan, Carcinoma by Activating the Hematopoietic NLRP3 Maxime Libert, Jean S. Fain, Carmen Guerra, Inflammasome Luc Bouwens, Mariano Barbacid, Frederic P. Lemaigre, A C Xi Wang, Yiqun Jia, Liling Wen, Wenxin Mu, and Patrick Jacquemin Xianrui Wu, Tao Liu, Xiangqi Liu, Juan Fang, This study generates new mouse models to study regulation Yizhao Luan, Ping Chen, Jinlong Gao, Ky-Anh Nguyen, of KRAS during pancreatic tumorigenesis and highlights a Jun Cui, Gucheng Zeng, Ping Lan, Qianming Chen, novel mechanism through which pancreatitis sensitizes Bin Cheng, and Zhi Wang acinar cells to Kras mutations. This study demonstrates that the periodontal pathogen P. gingivalis can promote colorectal tumorigenesis by recruiting myeloid cells and creating a proinflammatory tumor microenvironment.

TRANSLATIONAL SCIENCE 2788 “3G” Trial: An RNA Editing Signature to Guide Gastric Cancer Chemotherapy 2760 The Transcriptomic Landscape of Mismatch A C Omer An, Yangyang Song, Xinyu Ke, Jimmy Bok-Yan So, Repair-Deficient Intestinal Stem Cells Raghav Sundar, Henry Yang, Sun Young Rha, Prashant V. Bommi, Charles M. Bowen, Ming Hui Lee, Su Ting Tay, Xuewen Ong, Laura Reyes-Uribe, Wenhui Wu, Hiroyuki Katayama, Angie Lay Keng Tan, Matthew Chau Hsien Ng, Pedro Rocha, Edwin R. Parra, Alejandro Francisco-Cruz, Erwin Tantoso, Leilei Chen, Patrick Tan, Wei Peng Yong, Zuhal Ozcan, Elena Tosti, Jason A. Willis, Hong Wu, and Singapore Gastric Cancer Consortium (SGCC) Melissa W. Taggart, Jared K. Burks, Patrick M. Lynch, This study describes a novel A-to-I RNA editing signature as a Winfried Edelmann, Paul A. Scheet, Ignacio I. Wistuba, prognostic and predictive biomarker in advanced gastric Krishna M. Sinha, Samir M. Hanash, and Eduardo Vilar cancer, providing a new tool to improve patient stratification and response to therapy. The transcriptomic and proteomic profile of MMR-deficient intestinal stem cells displays a unique set of genes with potential roles as biomarkers of cancer initiation and early POPULATION AND PREVENTION SCIENCE progression. 2799 Bisphosphonate Use and Breast Cancer Risk among 2774 Heterogeneity and Clonal Evolution of Acquired PARP Women with Ductal Carcinoma In Situ Inhibitor Resistance in TP53- and BRCA1-Deficient Cells Christopher I. Li, Meghan R. Flanagan, Mei-Tzu C. Tang, € € Anniina Farkkila, Alfredo Rodríguez, Jaana Oikkonen, Peggy L. Porter, and Kathleen E. Malone Doga C. Gulhan, Huy Nguyen, Julieta Domínguez, This study finds that bisphosphonate use among women with Sandra Ramos, Caitlin E. Mills, Fernando Perez-Villatoro, a history of DCIS is associated with lower risk of subsequent Jean-Bernard Lazaro, Jia Zhou, Connor S. Clairmont, invasive breast cancer, providing a potential preventative Lisa A. Moreau, Peter J. Park, Peter K. Sorger, approach for this high-risk population. Sampsa Hautaniemi, Sara Frias, and Alan D. D’Andrea This study shows that BRCA1-deficient cells can give rise to multiple genomically and functionally heterogenous PARPi- resistant clones, which are associated with various vulnerabilities that can be targeted in a mechanism-specific manner.

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ABOUT THE COVER

POT1 is a member of the shelterin complex, which binds telomeres and regulates their extension. Germline mutations in POT1 confer increased risk to a host of cancers, including glioma. Using native mouse models of glioma, it was found that deletion of POT had sex-specific effects on tumorigenesis, with females exhibiting decreased survival compared to males. Transcriptomic analysis and immunostaining validation studies revealed sex-specific changes in immune populations, with females exhibiting decreased expression of microglia/macrophage markers. Artwork by Emma Vidal. For details, see article by Jalali and colleagues on page 2703.

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Cancer Res 2021;81:2575-2802.

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