Detection of House Dust Mite-derived DNA in Human Lung Tumors by Whole-Genome Sequencing

Lung cancer in never-smokers (LCINS) accounts for an increasing proportion of lung cancer cases, yet its risk factors remain poorly understood. House dust mites (HDM) are common aeroallergens that induce airway inflammation, but their potential contribution to lung cancer is unknown. We analyzed unmapped whole-genome sequencing reads from 783 lung cancers from the Sherlock-Lung (n = 621 never-smokers) and EAGLE (n = 162 smokers) cohorts, including 328 matched adjacent normal lung tissues. After removal of human sequences, reads were aligned to reference genomes from the two major HDM species and confirmed by BLAST. Samples with top BLAST matches were classified as HDM-detected. Associations between HDM detection and genomic, microbiome, and bulk RNA-seq-derived immune features were evaluated. HDM-derived DNA was detected at low abundance in a subset of tumors and adjacent normal tissues, with higher detection frequencies in tumors than matched normal tissues and in smokers than never-smokers. In LCINS tumors, HDM detection was not associated with tumor mutational burden or recurrent driver alterations but was associated with modest differences in immune cell composition and a limited but reproducible bacterial co-detection pattern. These findings provide a foundation for investigating aeroallergen-derived DNA signatures and their potential relationship to the lung tumor microenvironment.