Kathleen H. Burns

Dynamic and Ongoing De Novo L1 Retrotransposition Contributes to Genome Plasticity and Intrapatient Heterogeneity in Ovarian Cancer

Abstract Long interspersed element-1 (L1) retrotransposons are the only protein-coding active transposable elements in the human genome. Although typically silenced in normal cells, they are highly expressed in many human epithelial cancers, including high-grade serous ovarian cancer (HGSC), and can integrate into the genome through retrotransposition. De novo L1 insertions are known to contribute to genomic instability and cancer evolution in epithelial malignancies, including HGSC, suggesting that they might also play a role in intrapatient tumor heterogeneity. In this study, we quantified de novo L1 insertions in clinical HGSC specimens and uncovered high heterogeneity in total L1 insertion events (L1 burden) between patients. HGSC tumors with high L1 burden were highly proliferative, whereas tumors with low or no L1 insertions showed enrichment of immune response and cell death pathways. Although the overall L1 burden was similar across different tumor sites within the same patient, the specific L1 insertions (L1 profiles) diverged significantly more than their single-nucleotide variants profiles. Taken together, these findings demonstrate that L1 activity and retrotransposition are highly dynamic in vivo and can contribute substantially to tumor genome plasticity, especially at late stages of cancer progression. The patient-specific propensity of acquiring L1 insertions (L1 burden) could be driven by molecular properties of the progenitor tumor. Retrotransposition-associated DNA damage and/or replication stress could be a potential molecular vulnerability for precision cancer medicine approaches. Significance: L1 retrotransposition is a dynamic process that continues at late stages of high-grade serous ovarian cancer and can substantially contribute to intrapatient tumor heterogeneity.

Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker

Abstract Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. Although proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10−17 mol/L) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multianalyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multicancer biomarker with potential utility for disease detection and monitoring. Significance: The LINE-1 ORF1p transposon protein is pervasively expressed in many cancers and is a highly specific biomarker of multiple common, lethal carcinomas and their high-risk precursors in tissue and blood. Ultrasensitive ORF1p assays from as little as 25 μL plasma are novel, rapid, cost-effective tools in cancer detection and monitoring. See related commentary by Doucet and Cristofari, p. 2502. This article is featured in Selected Articles from This Issue, p. 2489