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bioRxiv · 10.1101/2025.10.03.680361

Pan-cancer analysis reveals context-dependent roles of LINE-1 ORF1p in immune regulation and copy number alterations

Kaparos, E. I.·Zhang, W.·Miyanaga, R.·McKerrow, W.·Boeke, J. D.·Davoli, T.·Mita, P.·Ruggles, K. V.·Fenyo, D.
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Abstract

L1 comprises 17% of the human genome, with 50-150 full-length sequences capable of retrotransposition. Although largely inactive in normal somatic tissues, tumorigenesis leads to L1 derepression and overexpression of its RNA binding chaperone protein, ORF1p. A potential cancer biomarker, ORF1p expression is a hallmark of multiple cancers and an early event in precursor lesions. Our study provides a comprehensive pan-cancer analysis of ORF1p using CPTAC proteogenomic data, revealing a dichotomous role in modulating immune responses. Integrated analyses and supervised learning models divide ORF1p-high tumors into two groups: (1) high ORF1p associates with immunosuppression, reduced interferon signaling and diminished immune cell infiltration (HNSCC and LSCC), and (2) ORF1p-high tumors associate with immune activation (UCEC). Linear regression models reveal that cancer-specific aneuploidies may underlie this immune dichotomy, highlighting the prognostic significance of ORF1p and informing new strategies to leverage detection of plasma-circulating ORF1p to enhance immunotherapeutic efficacy in different tumor contexts.

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Kaparos, E. I., Zhang, W., Miyanaga, R., McKerrow, W., Boeke, J. D., Davoli, T., Mita, P., Ruggles, K. V., Fenyo, D.. 2025-10-05. Pan-cancer analysis reveals context-dependent roles of LINE-1 ORF1p in immune regulation and copy number alterations. https://doi.org/10.1101/2025.10.03.680361

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