Abstract 4734: Nasopharyngeal carcinoma molecular subgroups for somatic copy number alterations (SCNAs)
Authors: Wei Dai, Dittman Lai-Shun Chung, Larry Ka-Yue Chow, Merrin Man-Long Leong, Candy King-Chi Chan, Josephine Mun-Yee Ko, Maria Li Lung
Journal: Cancer Research (2020)

Abstract Background: Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of the inter-patient heterogeneity and identify new therapeutic targets. Although multiple genomic studies have been carried out in nasopharyngeal carcinoma (NPC), the detailed mechanisms underlying these genetic alterations and NPC pathogenesis remain unclear. Aims: We aim to identify the additional genetic events driving tumorigenesis by increasing the statistical power to distinguish the infrequent driver events from passengers, gain insights in the mechanisms underlying genetic alterations and evaluate their prognostic value for overall survival. Our ultimate goal is to identify potential new therapeutic targets for NPC treatment. Methods: We performed an integrative genomic and transcriptomic analysis for a total of 216 NPC cases from three genomics studies to catalogue the somatic mutational signatures, somatic copy number alterations (SCNAs) and gene expression changes in NPC. Results: Three clusters with distinct SCNA patterns were uncovered. Cluster 1 (SCNA-L-gain), accounting for 66.7% of total cases, has consistent CN loss in chromosomes 3, 14 and 16, which are typical SCNAs in NPC; Cluster 2 (SCNA-M-gain, 8.2%) is characterized as a moderate level of CN gain involved in selected chromosomes 17, 19 and 22. Strikingly, Cluster 3 (SCNA-H-gain, 25.1%) has extensive CN gains across the genome with regional loss near telomeres in several chromosomes. Noticeably, a new mutational signature relevant to the deficiency of the homologous recombination (HR) repair pathway (BRCAness) was discovered in a subset of NPC cases (29.6%). The survival analysis indicates that this mutational signature is significantly associated with shorter overall survival after adjustment for stage, gender and age and stratification by studies (P=0.018, HR=2.2, 95% CI 1.1-4.4). All the cases harboring the pathogenic BRCA2 germline and somatic mutations carry this mutational signature, but only account for 7.8% of such cases. A strong BRCAness signature is more frequently found in the SCNA-H-gain cluster (P=0.012), indicating HR deficiency may play a role for genomic instability in this subset of NPC patients. Conclusions: In NPC, there is a molecular subtype with extensively high copy number gain and a strong BRCAness signature. Discovery of this molecular subtype supports prospective clinical trials investigating agents, such as PARP inhibitor, to target this subset of patients. Acknowledgements: This study was funded by the Hong Kong Research Grants Council grant (AoE/M-06/08) to MLL Citation Format: Wei Dai, Dittman Lai-Shun Chung, Larry Ka-Yue Chow, Merrin Man-Long Leong, Candy King-Chi Chan, Josephine Mun-Yee Ko, Maria Li Lung. Nasopharyngeal carcinoma molecular subgroups for somatic copy number alterations (SCNAs) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4734.