Lung Microbial and Host Genomic Signatures as Predictors of Prognosis in Early-Stage Adenocarcinoma.

Abstract

Risk of early-stage lung adenocarcinoma recurrence after surgical resection is significant, and the postrecurrence median survival is approximately 2 years. Currently, there are no commercially available biomarkers that predict recurrence. In this study, we investigated whether microbial and host genomic signatures in the lung can predict recurrence. In 91 patients with early-stage (stage IA/IB) lung adenocarcinoma with extensive follow-up, we used 16s rRNA gene sequencing and host RNA sequencing to map the microbial and host transcriptomic landscape in tumor and adjacent unaffected lung samples. Of 91 subjects, 23 had tumor recurrence over 5-year period. In tumor samples, lung adenocarcinoma recurrence was associated with enrichment in Dialister and Prevotella, whereas in unaffected lung samples, recurrence was associated with enrichment in Sphingomonas and Alloiococcus. The strengths of the associations between microbial and host genomic signatures with lung adenocarcinoma recurrence were greater in adjacent unaffected lung samples than in the primary tumor. Among microbial-host features in the unaffected lung samples associated with recurrence, enrichment in Stenotrophomonas geniculata and Chryseobacterium was positively correlated with upregulation of IL2, IL3, IL17, EGFR, and HIF1 signaling pathways among the host transcriptome. In tumor samples, enrichment in Veillonellaceae (Dialister), Ruminococcaceae, Haemophilus influenzae, and Neisseria was positively correlated with upregulation of IL1, IL6, IL17, IFN, and tryptophan metabolism pathways. Overall, modeling suggested that a combined microbial/transcriptome approach using unaffected lung samples had the best biomarker performance (AUC = 0.83). This study suggests that lung adenocarcinoma recurrence is associated with distinct pathophysiologic mechanisms of microbial-host interactions in the unaffected lung rather than those present in the resected tumor.