Impaired TGF-ß signaling via AHNAK family mutations elicits an esophageal cancer subtype with sensitivities to genotoxic therapy and immunotherapy.

BACKGROUND: Genome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear. METHODS: Here, we aimed to characterize genomic events representing specific mechanisms of GI based on 201 ESCC samples and validated our findings at the patient, single-cell and cancer cell-line levels, including a newly generated multi-omics dataset of the trial NCT04006041. RESULTS: A two-gene (AHNAK and AHNAK2) mutation signature was identified to define the "AHNAK1/2-mutant" cancer subtype. Single-cell-assisted multi-omics analysis showed that this subtype had a higher neoantigen load, active antigen presentation, and proficient CD8 + T cell infiltrations, which were validated at pan-cancer levels. Mechanistically, AHNAK1/2-mutant ESCC was characterized by impaired response of TGF-ß and the inefficient alternative end-join repair (Alt-EJ) that might promote GI. Knockdown of AHNAK in ESCC cell lines resulted in more Alt-EJ events and increased sensitivities to cisplatin. Furthermore, this two-gene signature accurately predicted better responses to DNA-damaging therapy in various clinical settings (HR ≈ 0.25). The two-gene signature predicted higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment. Finally, a molecular classification scheme was built and outperformed established molecular typing models in the prognosis stratification of ESCC patients. CONCLUSION: Our study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.

Feasibility of injecting Fluorescent Agent under the Guidance of Electromagnetic Navigation Bronchoscopy in Pulmonary Nodule Resection / 中国肺癌杂志

BACKGROUND@#It is a great challenge for surgeons to resect pulmonary nodules with small volume, deep position and no solid components under video-assisted thoracoscopic surgery. The purpose of this study is to explore the feasibility and necessity of the localization of pulmonary nodules by injecting indocyanine green (ICG) under the guidance of magnetic navigation bronchoscope and the resection of small pulmonary nodules under the fluoroscope.@*METHODS@#Between December 2018 and August 2019, sixteen consecutive patients with 30 peripheral lung lesions in our hospital received fluorescent thoracoscopic pulmonary nodule resection. Electromagnetic navigation bronchoscope (ENB) was performed before surgery to guide ICG to the target lesion.@*RESULTS@#All patients underwent magnetic navigation-guided pulmonary nodule localization, and surgical resection was performed immediately after localization was completed. The average size of the nodules was (11.12±3.65) mm. The average navigation time was (12.06±2.74) minutes, and the average interval between dye labeling and lung resection was (25.00±5.29) minutes. All lesions were completely resected, the localization success rate was 100.00%, no bleeding and other complications occurred after the localization, the postoperative pathological results confirmed the accuracy of the staining.@*CONCLUSIONS@#Indocyanine green injection under the guidance of magnetic navigation bronchoscope is an effective way to locate pulmonary nodules, which can locate small and untouchable lesions in the lung. This method can help surgeons identify lesions more quickly and accurately. It is practical and worthy of promotion.