Comprehensive characterization of platelets transcriptome for diagnosis and clinical management of cancer patients
Authors:   , D'Ambrosi Silvia 
Published: August 2024

This PhD thesis investigates platelet RNA signatures as a novel approach for developing liquid biopsy tests for early cancer detection. Traditionally known for their role in hemostasis, platelets also play significant roles in cancer progression and development. Cancer cells can alter platelet RNA content, and these changes have potential as biomarkers for non-invasive cancer diagnostics.
Chapter 2 reviews the relationship between platelets and cancer, highlighting the promise of platelet RNA profiles as biomarkers. Understanding this relationship could lead to accurate, non-invasive diagnostic tools for cancer detection and management.
Chapter 3 addresses the use of the established thromboSeq pipeline to develop a new test for early cancer detection and monitoring. The new classifier includes a larger number of earlier-stage NSCLC samples to improve detection rates for locally-advanced (I-III) cancers without compromising detection rates for late-stage (IV) disease. By adjusting the threshold of the TEP score, two distinct blood tests were proposed: HighSpec, optimized for positive predictive value (PPV) to reduce false positives, and HighSens, optimized for negative predictive value (NPV) to reduce false negatives.
Early cancer detection is crucial for better treatment outcomes. Chapter 4 showcases the thromboSeq pipeline's ability to detect 18 cancer types with 99% specificity and accurately identify tumor origins, highlighting the potential of TEP-derived RNA as a screening tool.
Platelets are enriched with circRNAs, which are stable, resistant to degradation, and differentially expressed in various cancer types, making them promising cancer biomarkers. Chapter 5 highlights changes in platelet circRNA profiles in NSCLC patients, identifying 411 significantly differentially expressed circRNAs. Additionally, circNRIP1 was identified as a possible biomarker candidate for lung cancer progression.
Despite the wide range of transcriptomic profiles found in liquid biopsies, many studies only use one type of RNA as a potential diagnostic biomarker. Chapter 6 examines the use of a combination of biomarkers, which may lead to more accurate diagnoses. This study explores how combining circRNA and mRNA signatures from platelets could improve lung cancer detection.
Liquid biopsy tests are also valuable for monitoring cancer progression, particularly in hard-to-detect metastases, such as those in the central nervous system (CNS). Chapter 7 reviews the potential of liquid biopsies, including various biosources like CTCs, circulating DNA/RNA, extracellular vesicles, and TEPs, to overcome the limitations of traditional neuroimaging and tissue biopsy. These methods may allow non-invasive, repeated sampling of tumor-derived material, improving diagnostic accuracy and monitoring disease progression.
Overall, TEPs are a promising biosource for blood-based liquid biopsies. TEPs have the potential to revolutionize cancer diagnostics and management by enabling the development of minimally invasive tests that can improve patient outcomes and facilitate clinical decision-making.