Molecular subtyping of small-cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies

Small-cell lung cancer (SCLC) is an exceptionally lethal malignancy characterized by extremely high alteration rates and tumor heterogeneity, which limits therapeutic options. In contrast to non-small-cell lung cancer that develops rapidly with precision oncology, SCLC still remains outside the realm of precision medicine. No recurrent and actionable mutations have been detected. Additionally, a paucity of substantive tumor specimens has made it even more difficult to classify SCLC subtypes based on genetic background. We therefore carried out whole-exome sequencing (WES) on the largest available Chinese SCLC cohort. For the first time, we partitioned SCLC patients into three clusters with different genomic alteration profiles and clinical features based on their mutational signatures. We showed that these clusters presented differences in intratumor heterogeneity and genome instability. Moreover, a wide existence of mutually exclusive gene alterations, typically within similar biological functions, was detected and suggested a high SCLC intertumoral heterogeneity. Particularly, Cluster 1 presented the greatest potential to benefit from immunotherapy, and Cluster 3 constituted recalcitrant SCLC, warranting biomarker-directed drug development and targeted therapies in clinical trials. Our study would provide an in-depth insight into the genome characteristics of the Chinese SCLC cohort, defining distinct molecular subtypes as well as subtype-specific therapies and biomarkers. We propose tailoring differentiated therapies for distinct molecular subgroups, centering on a personalized precision chemotherapy strategy combined with immunization or targeted therapy for patients with SCLC.

Automated summary

This study used whole-exome sequencing to divide small-cell lung cancer (SCLC) patients in a Chinese cohort into three clusters based on their genomic alteration profiles and clinical features. The study found differences in intratumor heterogeneity and genome instability among these clusters, as well as mutually exclusive gene alterations within similar biological functions. Cluster 1 showed the potential to benefit from immunotherapy, while Cluster 3 constituted recalcitrant SCLC, suggesting the need for biomarker-directed drug development and targeted therapies.