Multiomic Characterization of Stage I Lung Adenocarcinoma Reveals Distinct Genetic and Immunologic Features of Recurrent Disease

Kratz, J. R.; Li, J. Z.; Tsui, J.; Lee, J. C.; Ding, V. W.; Rao, A. A.; Mann, M. J.; Chan, V.; Combes, A. R.; Krummel, M. F.; Jablons, D. M.

doi:10.1101/2021.05.20.444915

bioRxiv · 10.1101/2021.05.20.444915

Multiomic Characterization of Stage I Lung Adenocarcinoma Reveals Distinct Genetic and Immunologic Features of Recurrent Disease

Kratz, J. R.·Li, J. Z.·Tsui, J.·Lee, J. C.·Ding, V. W.·Rao, A. A.·Mann, M. J.·Chan, V.·Combes, A. R.·Krummel, M. F.·Jablons, D. M.

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Abstract

BackgroundRecurrence after surgery for early-stage lung cancer is common, occurring between 30-50% of the time. Despite the popularization of prognostic gene signatures in early-stage lung cancer that allow us to better predict which patients may recur, why patients recur after surgery remains unclear. MethodsUsing a large cohort of lung adenocarcinoma patients with complete genetic, genomic, epigenetic and clinical profiling, a recurrence classifier was developed which identifies patients at highest risk of recurrence. The genetic, genomic, and epigenetic profiles of stage I patients with low-vs. high-risk of recurrence were compared. To characterize the tumor immune microenvironment of recurrent stage I tumors, single cell RNA-seq was performed on fresh tissue samples undergoing lung adenocarcinoma resection at UCSF to identify unique immune population markers and applied to the large stage I lung adenocarcinoma cohort using digital cytometry. ResultsRecurrence high-risk stage I lung adenocarcinomas demonstrated a higher mutation burden than low-risk tumors, however, none of the known canonical lung cancer driver mutations were more prevalent in high-risk tumors. Transcriptomic analysis revealed widespread activation of known cancer and cell cycle pathways with simultaneous downregulation of immune response pathways including antigen presentation and Th1/Th2 activation. Tumors at high-risk of recurrence displayed depleted adaptive immune populations, and depletion of adaptive immune populations was independently prognostic of recurrence in stage I lung adenocarcinomas. ConclusionRecurrent stage I lung adenocarcinomas display distinct features of genomic and genetic instability including increased tumor mutation burden, neoantigen load, activation of numerous mitotic and cell cycle genes, and decreased genome-wide methylation burden. Relative depletion of infiltrating adaptive immune populations may allow these tumors to escape immunosurveillance and recur after surgery.

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Kratz, J. R., Li, J. Z., Tsui, J., Lee, J. C., Ding, V. W., Rao, A. A., Mann, M. J., Chan, V., Combes, A. R., Krummel, M. F., Jablons, D. M.. 2021-05-21. Multiomic Characterization of Stage I Lung Adenocarcinoma Reveals Distinct Genetic and Immunologic Features of Recurrent Disease. https://doi.org/10.1101/2021.05.20.444915

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