Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

Cell reports. 2018 Apr 03 [Epub]

Joshua D Campbell, Christina Yau, Reanne Bowlby, Yuexin Liu, Kevin Brennan, Huihui Fan, Alison M Taylor, Chen Wang, Vonn Walter, Rehan Akbani, Lauren Averett Byers, Chad J Creighton, Cristian Coarfa, Juliann Shih, Andrew D Cherniack, Olivier Gevaert, Marcos Prunello, Hui Shen, Pavana Anur, Jianhong Chen, Hui Cheng, D Neil Hayes, Susan Bullman, Chandra Sekhar Pedamallu, Akinyemi I Ojesina, Sara Sadeghi, Karen L Mungall, A Gordon Robertson, Christopher Benz, Andre Schultz, Rupa S Kanchi, Carl M Gay, Apurva Hegde, Lixia Diao, Jing Wang, Wencai Ma, Pavel Sumazin, Hua-Sheng Chiu, Ting-Wen Chen, Preethi Gunaratne, Larry Donehower, Janet S Rader, Rosemary Zuna, Hikmat Al-Ahmadie, Alexander J Lazar, Elsa R Flores, Kenneth Y Tsai, Jane H Zhou, Anil K Rustgi, Esther Drill, Ronglei Shen, Christopher K Wong, Cancer Genome Atlas Research Network , Joshua M Stuart, Peter W Laird, Katherine A Hoadley, John N Weinstein, Myron Peto, Curtis R Pickering, Zhong Chen, Carter Van Waes

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Boston University School of Medicine, Boston, MA 02118, USA., Department of Surgery, University of California, San Francisco, San Francisco, CA 94115, USA; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA., Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada., Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Medicine-Biomedical Informatics Research, Stanford University, Stanford, CA 94305, USA., Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA., Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA., Department of Public Health Sciences, Penn State Milton Hershey Medical Center, Hershey, PA 17033, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Medicine and Dan L Duncan Comprehensive Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX 77030, USA., Department of Molecular & Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA., Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97201, USA., Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA., Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Hudson Alpha Institute for Biotechnology, Huntsville, AL 35806, USA., Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA., Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Medicine-Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Department of Biology & Biochemistry, UH-SeqNEdit Core, University of Houston, Houston, TX 77204, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Center for Comparative Medicine, Baylor College of Medicine, Houston, TX 77030, USA., Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA., University of Oklahoma Health Sciences Center, Department of Pathology, Oklahoma City, OK 73104, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Departments of Pathology, Genomic Medicine, Dermatology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77401, USA., Molecular Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA., Departments of Anatomic Pathology and Tumor Biology, Moffitt Cancer Center, Tampa, FL 33612, USA., Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Biomolecular Engineering, Center for Biomolecular Sciences and Engineering University of California, Santa Cruz, Santa Cruz, CA 95064, USA., Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA. Electronic address: ., Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA. Electronic address: .