Abstract 3488: RNA-sequencing reveals etiology-specific dysregulation of PIWI-interacting RNAs in head and neck squamous cell carcinoma
Authors: Krishnan Aswini R. , Korrapati Avinaash , Zou Angela E. , Qu Yuanhao , Li Pin xue , Zheng Hao , Kwok James , Ongkeko Weg M. 
Published: July 2017

Head and neck squamous cell carcinoma (HNSCC) represents the sixth deathliest cancer worldwide and the second fastest growing cancer in many developing countries. A cancer characterized by heterogeneity, HNSCCs are known to display varied genetic alterations based on a variety of epidemiological and clinical factors, including etiology, making it challenging to comprehensively profile and treat the disease. New studies have shown that non-coding RNAs (ncRNAs) may provide a promising means by which to explore HNSCC pathogenesis due to their diverse genetic and epigenetic roles and their recent emergence as potential biomarkers for cancer. In this study, we decided to investigate etiology-specific alterations of PIWI-interacting RNAs (piRNAs), the largest class of ncRNAs that have roles in silencing of retrotransposons, heterochromatin modification, and germ cell maintenance, in HNSCC. We particularly focused on smoking, the most prevalent risk factor of HNSCC, and HPV, the fastest growing cause of the disease today. Using 466 HNSCC RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), we identified 58 piRNAs significantly differentially expressed in HNSCC current smokers vs. normal lifelong nonsmokers and 39 piRNAs significantly dysregulated in HNSCC HPV16(+) vs. normal HPV(-) cohorts, with 29 piRNAs commonly implicated in both etiologies (p &lt; 0.05). Of the 58 piRNAs implicated in smoking-related HNSCC, 4 piRNAs were found to significantly associate with clinical variables and 1 transcript with patient outcome, with similar results for HPV-mediated piRNA dysregulation (Kruskal-Wallis, Cox regression, p &lt; 0.05). In particular, we recognized transcripts NONHSAT081250, NONHSAT123636, and NONHSAT108298 for their correlations with tumor stage, metastatic status, and/or anatomic site, as well as presence of common mutations and copy number variations in HNSCC. We then analyzed mRNA expression data for the same 466 samples from TCGA and found PIWI proteins PIWIL1 and PIWIL2 to be implicated in smoking-related and HPV-related HNSCCs respectively, and also to associate with piRNA candidate expression levels (p &lt; 0.05). We subsequently validated the dysregulation of all significant piRNA and PIWI protein candidates in vitro in cigarette-treated and HPV E6/E7-overexpressing normal oral epithelial cells. While a comprehensive understanding of the functional and mechanistic relevance of a vast majority of non-coding transcripts remains yet to be found, our findings reveal the potential of these genes to mediate a variety of etiology-specific clinical and genomic aberrancies in HNSCC and provide novel insights to thwart the progression of this disease.

Citation Format: Aswini R. Krishnan, Avinaash Korrapati, Angela E. Zou, Yuanhao Qu, Pin xue Li, Hao Zheng, James Kwok, Weg M. Ongkeko. RNA-sequencing reveals etiology-specific dysregulation of PIWI-interacting RNAs in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3488. doi:10.1158/1538-7445.AM2017-3488