JD Campbell, C Yau, R Bowlby, Y Liu, K Brennan, H Fan, AM Taylor, C Wang, V Walter, R Akbani, LA Byers, CJ Creighton, C Coarfa, J Shih, AD Cherniack, O Gevaert, M Prunello, H Shen, P Anur, J Chen, H Cheng, DN Hayes, S Bullman, CS Pedamallu, AI Ojesina, S Sadeghi, KL Mungall, AG Robertson, C Benz, A Schultz, RS Kanchi, CM Gay, A Hegde, L Diao, J Wang, W Ma, P Sumazin, H-S Chiu, T-W Chen, P Gunaratne, L Donehower, JS Rader, R Zuna, H Al-Ahmadie, AJ Lazar, ER Flores, KY Tsai, JH Zhou, AK Rustgi, E Drill, R Shen, CK Wong, Cancer Genome Atlas Research Network, JM Stuart, PW Laird, KA Hoadley, JN Weinstein, M Peto, CR Pickering, Z Chen, C Van Waes
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.