Identification of Novel Molecular Subtypes to Improve the Classification Framework of Nasopharyngeal Carcinoma

Abstract

Background: Nasopharyngeal carcinoma (NPC) treatment is largely based on the 'one drug fits all' strategy that is used for patients who display similar pathological characteristics. However, due to its biological heterogeneity, NPC patients with the same clinical stage or similar therapeutic strategies exhibit significant clinical differences. Thus, the identification of new molecular subgroups in NPC patients based on these characteristics may eventually lead to better therapeutic outcomes.

Methods: In this study, 192 NPC samples with the corresponding clinicopathological information were collected from Fujian Cancer Hospital, between January 2015 and January 2018. Besides, 6 normal nasopharyngeal epithelial tissue samples from chronic nasopharyngitis patients were also collected. RNA sequence was conducted to obtain the gene expression profile of these samples. Consensus clustering was further applied to identify molecular subtypes. External NPC cohort (GSE102349) was used as the validation set. The radiation (IR)-sensitive and IR-resistant NPC cell lines were also examined using metabolomics analysis.

Findings: We demonstrate that NPC patients could be classified into immune, metabolism, and proliferation molecular subtypes with distinct clinical features. It was also noted that this classification was repeatable as well as predictable by validating the external NPC cohorts. Besides, metabolomics showed that the arachidonic acid metabolites were associated with the radiation resistance of NPC. We also identify several key genes among each subtype using weighted correlation network analysis (WGCNA). Furthermore, a prognostic model based on these key genes was developed and validated, and it showed a high prognosis-predictive ability.

Interpretation: This study presents a novel classification of nasopharyngeal carcinoma (immune, metabolism, and proliferation subtypes) based on transcriptomics, which demonstrates significant value in predicting survival in NPC patients as well as presents opportunities for therapeutic development.

Funding: This work was supported by the grants of Science and Technology Program of Fujian Province, China (2018Y2003); Fujian Provincial Clinical Research Center for Cancer Radiotherapy and Immunotherapy (2020Y2012); the National Clinical Key Specialty Construction Program (2021); Fujian Clinical Research Center for Radiation and Therapy of Digestive, Respiratory and Genitourinary Malignancies; United Fujian Provincial Health and Education Project for Tackling the Key Research, China (2019 WJ-03); National Natural Science Foundation of China (11974077; 82072986; 82103059); Major Research Projects for Young and Middle-aged Researchers of Fujian Provincial Health Commission (2021ZQNZD010); Science and Technology Pilot Program of Fujian Province, China (2021Y0053); Wu Jieping Medical Foundation (320.6750.2021-01-27); Joint Funds for the Innovation of Science and Technology, Fujian province (2021Y9196); High-level Talent Training Program of Fujian Cancer Hospital (2022YNG07); Innovative Medicine Subject of Fujian Provincial Health Commission, China (2021CXA029); Shanghai Sailing Program (20YF1428000); and Pudong New Area Science and Technology Development Fund (PKJ2021-Y45).

Declaration of Interest: The authors declare no competing interests.

Ethical Approval: This study was authorized by the ethics committee of Fujian Cancer Hospital (Fuzhou, China; numbers K2022-084-01). Each patient was asked to grant their written and informed consent before participating in any study-specific research.

Keywords: Nasopharyngeal carcinoma, Molecular subtypes, Transcriptomic, Prognosis signature