Abstract 5346: Recurrent genomic copy alterations deregulate the transcriptome and key signaling networks in head and neck cancer cell lines and tumors with worse prognosis

Abstract

Abstract Human cancer cell lines have been important tools for biological and preclinical investigation, and establishing their relationship to genomic alterations and subtypes found in tumors could further accelerate functional and therapeutic discoveries. We conducted an integrated analysis of the genomic and transcriptomic profiles of 15 human papillomavirus negative (HPV−) and 11 HPV(+) head and neck squamous cell carcinoma (HNSCC) lines, to identify models of important molecular subtypes uncovered among 279 HNSCC tumors from The Cancer Genome Atlas (TCGA). We developed analytic approaches to detect copy number alterations (CNAs) driving altered expression and predict deleterious mutations in HNSCC lines for comparison with TCGA. Strikingly, HNSCC lines displayed recurrent amplifications on chromosomes 3q22-29, 5p15, 11q13/22, and 8p11 that drive increased expression of a cluster of ~100 mRNAs encoding multiple known and understudied candidate oncogenes. These CNAs, together with loss and under-expression or mutations of putative tumor suppressor genes, recapitulate genomic alterations found in more aggressive HNSCC tumor subtypes. Among these, concurrent 3q26.3 amplification and TP53 mutation in HPV(−) HNSCCs is associated with worse overall survival. Common and distinctive CNAs, transcriptome, and mutations converge on biologically and therapeutically important signal pathways and functions in HNSCCs differing in HPV status, including PI3K, Hippo, TGF-β, Wnt/β-catenin, TP63, TP53/death, cell cycle/mitosis, stemness/differentiation, chromatin remodelling/DNA replication, post-transcriptional regulation, and mitochondrial biosynthesis. Our findings elucidate and validate genomic alterations underpinning numerous discoveries made with historic and recently derived HNSCC lines, and provide valuable models for future preclinical and therapeutic studies in subsets of HNSCCs with worse prognosis. Supported by NIDCD/NIH intramural projects ZIA-DC-000073, ZIA-DC-000074. This work utilized the computational resources of the NIH HPC Biowulf cluster. (http://hpc.nih.gov) Citation Format: Hui Cheng, Xinping Yang, Han Si, Anthony Saleh, Wenming Xiao, Jamie Coupar, Susanne M. Gollin, Robert L. Ferris, Natalia Issaeva, Wendell G. Yarbrough, Mark E. Prince, Thomas E. Carey, Carter Van Waes, Zhong Chen. Recurrent genomic copy alterations deregulate the transcriptome and key signaling networks in head and neck cancer cell lines and tumors with worse prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5346.