From rags to riches : cell-free RNA analysis for non-invasive cancer detection and characterization
Abstract/Contents
- Abstract
- Cell-free RNA (cfRNA) analysis could allow non-invasive tumor gene expression profiling and monitoring of cancers. Here, we describe RARE-Seq (Random priming & Affinity capture of cell-free RNA fragments for Enrichment analysis by Sequencing), a novel cfRNA profiling platform optimized for the simultaneous noninvasive detection of tissue-derived transcripts and associated somatic mutations. We show that platelet contamination can substantially confound cfRNA analyses and describe a framework to overcome it. In analytical validations, we find RARE-Seq to be ~50-fold more sensitive for detecting tumor-derived transcriptomes than whole transcriptome strategies, corresponding to a limit of detection of 0.05%. To explore the clinical utility of RARE-Seq, we profiled 269 samples from 201 individuals with cancer or non-malignant conditions and controls. Detection of non-small cell lung cancer (NSCLC) expression signatures in cfRNA increased with stage, ranging from 40% in stage I to 87% in stage IV, with driver somatic mutations detectable in cfRNA from 44% of stage IV patients. When applied to EGFR mutant NSCLC patients who developed resistance to tyrosine kinase inhibitors, RARE-Seq detected both histologic transformation and mutation-based resistance mechanisms. Furthermore, RARE-Seq detected other solid tumor types and identified tissue of origin with high accuracy. Lastly, we demonstrate the potential utility of RARE-Seq for assessing benign pulmonary conditions and tracking response to mRNA vaccines. Together, these results highlight the potential value of ultrasensitive cfRNA analysis and provide proof-of-concept for multiple potential clinical applications.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2024; ©2024 |
| Publication date | 2024; 2024 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Nesselbush, Monica Christine |
|---|---|
| Degree supervisor | Diehn, Maximilian |
| Thesis advisor | Diehn, Maximilian |
| Thesis advisor | Alizadeh, Ash |
| Thesis advisor | Gentles, Andrew J |
| Degree committee member | Alizadeh, Ash |
| Degree committee member | Gentles, Andrew J |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Monica C. Nesselbush. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2024. |
| Location | https://purl.stanford.edu/wx828cp9031 |
Access conditions
- Copyright
- © 2024 by Monica Christine Nesselbush
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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