Identification of novel molecular subtypes to improve the classification framework of nasopharyngeal carcinoma.

ABSTRACT

BACKGROUND: Nasopharyngeal carcinoma (NPC) treatment is largely based on a 'one-drug-fits-all' strategy in patients with similar pathological characteristics. However, given its biological heterogeneity, patients at the same clinical stage or similar therapies exhibit significant clinical differences. Thus, novel molecular subgroups based on these characteristics may better therapeutic outcomes. METHODS: Herein, 192 treatment-naïve NPC samples with corresponding clinicopathological information were obtained from Fujian Cancer Hospital between January 2015 and January 2018. The gene expression profiles of the samples were obtained by RNA sequencing. Molecular subtypes were identified by consensus clustering. External NPC cohorts were used as the validation sets. RESULTS: Patients with NPC were classified into immune, metabolic, and proliferative molecular subtypes with distinct clinical features. Additionally, this classification was repeatable and predictable as validated by the external NPC cohorts. Metabolomics has shown that arachidonic acid metabolites were associated with NPC malignancy. We also identified several key genes in each subtype using a weighted correlation network analysis. Furthermore, a prognostic risk model based on these key genes was developed and was significantly associated with disease-free survival (hazard ratio, 1.11; 95% CI, 1.07-1.16; P < 0.0001), which was further validated by an external NPC cohort (hazard ratio, 7.71; 95% CI, 1.39-42.73; P < 0.0001). Moreover, the 1-, 3-, and 5-year areas under the curve were 0.84 (95% CI, 0.74-0.94), 0.81 (95% CI, 0.73-0.89), and 0.82 (95% CI, 0.73-0.90), respectively, demonstrating a high predictive value. CONCLUSIONS: Overall, we defined a novel classification of nasopharyngeal carcinoma (immune, metabolism, and proliferation subtypes). Among these subtypes, metabolism and proliferation subtypes were associated with advanced stage and poor prognosis of NPC patients, whereas the immune subtype was linked to early stage and favorable prognosis.