Abstract 3939: The genomic landscape of nasopharyngeal carcinoma
Authors: LIN DECHEN , Meng Xuan , Hazawa Masaharu , Nagata Yasunobu , Varela Ana Maria , Xu Liang , Sato Yusuke , Liu Li-Zhen , Ding Ling-Wen , Sharma Arjun , Goh Boon Cher , Lee Soo Chin , Petersson Bengt Fredrik , Yu Feng Gang , Macary Paul , Oo Min Zin , Chan Soh Ha , Yang Henry , Ogawa Seishi , Koeffler H. Phillip 
Published: August 2015

Background Nasopharyngeal carcinoma (NPC) arises from the epithelial tissue of the nasopharynx. This cancer has remarkable ethnic and geographic distributions, with a particularly high prevalence in Southern China and Southeast Asia. Genetic susceptibility and Epstein-Barr virus infections have been implicated in the pathogenesis of NPC. However, genomic abnormalities of this neoplasm remain largely obscure, and no effective targeted therapy has been established. Therefore, a strong need exists to characterize the genetic alterations of this type of tumour for guiding the development of more effective and innovative therapeutic regimens.

Methods Whole exomes sequencing (WES) was performed on 56 NPC germline/tumor pairs and 5 NPC cell lines. Transcriptome sequencing (RNA-seq) was conducted on 4 tumors from this cohort. An additional 61 NPC germline/tumor pairs and 5 non-paired primary tumors were further subjected to targeted regional deep-sequencing (TS). The somatic copy number variations (SCNV) of 52 primary tumors were profiled by SNP-array hybridization (50 of them also had WES data). Finally, both in vitro and in vivo biological and biochemical experiments were performed to evaluate the newly-identified mutations in NPC cell lines.

Results We identified a total of 1,577 non-silent somatic mutations affecting 1,413 genes from WES, revealing a relatively low mutational rate and wide mutational diversity. Integration of the results from WES, TS and RNA-seq revealed a distinct mutational signature and a number of significantly mutated genes (such as TP53, ARID1A, MLL2, BAP1, PIK3CA, etc.) in NPC. Pathway enrichment analysis of genetic lesions identified several important cellular processes and pathways in NPC including chromatin modification, ERBB-PI3K signaling and autophagy machinery. We further characterized the biological functions of both ARID1A and BAP1 proteins in NPC cell lines. Depletion of wild-type endogenous ARID1A expression with shRNAs resulted in increased anchorage-independent colony formation, cell migration and xenograft growth in vivo, whereas ectopically expressed ARID1A suppressed both cell proliferation and migration. Similarly, ectopic expression of wild-type BAP1 suppressed anchorage-independent colony formation of NPC cells.

Conclusion We characterized the genomic landscape of 128 NPC cases, and identified a number of novel driver genes with statistical and biological evidence. Integrated analysis showed enrichment of genetic lesions affecting chromatin modification, ERBB-PI3K signaling and autophagy machinery, offering opportunities for developing novel treatments. These results in aggregate provide an important genetic foundation for further study of the molecular pathology and etiology of this fatal disease.

Citation Format: DECHEN LIN, Xuan Meng, Masaharu Hazawa, Yasunobu Nagata, Ana Maria Varela, Liang Xu, Yusuke Sato, Li-Zhen Liu, Ling-Wen Ding, Arjun Sharma, Boon Cher Goh, Soo Chin Lee, Bengt Fredrik Petersson, Feng Gang Yu, Paul Macary, Min Zin Oo, Soh Ha Chan, Henry Yang, Seishi Ogawa, H. Phillip Koeffler. The genomic landscape of nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3939. doi:10.1158/1538-7445.AM2015-3939