Greco, Lorenza (2020) Next Generation Sequencing for gene fusions detection in Non Small Cell Lung Cancer. [Tesi di dottorato]

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Non Small Cell Lung Cancer (NSCLC) represents the most leading cause of death for cancer worldwide.1 In addition to standard care (chemotherapy), several clinical trials demonstrated the efficacy in advanced stage (IIIB-IV) NSCLC patients of targeted treatment, represented by tyrosine kinase inhibitors (TKIs).2 For this reason, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC) and the Association for Molecular Pathology (AMP) established, in addition to epidermal growth factor receptor (EGFR) molecular assessment, a panel of “must test genes” that includes also gene fusions, such as Anaplastic Lymphoma Kinase (ALK) and ROS Proto-Oncogene 1 Receptor Tyrosine Kinase (ROS1).3 On the overall, other clinically relevant gene rearrangements involving REarranged during Transfection (RET) and neurotrophic receptor tyrosine kinase (NTRK) genes 1, 2, and 3 showed their feasibility as targetable biomarkers in NSCLC patients.4,5 For predictive molecular analysis, tissue represents the most suitable sample type in diagnostic routine, but in NSCLC setting tissue specimens are often characterized by scant amount of nucleic acids on which molecular analysis may be performed. For this reason, very sensitive methodologies such as Next Generation Sequencing (NGS) and nanofluidic color-code barcode systems (Nanostring) should be implemented in clinical practice. Unfortunately, despite of NGS approach, a not negligible percentage of NSCLC patients (20-25%) cannot be analyzed for the quality and quantity limitations of “scant” samples. In this setting, “liquid biopsy” may represent a valid diagnostic tool to satisfy clinical needs.6,7 Liquid biopsy was clinically approved for the detection of sensitive mutations in EGFR when tissue is not available at basal or for acquired resistance mutation p.T790M after first line of TKIs treatments in NSCLC patients, unfortunately tissue specimen represents the only biological source to test clinically relevant gene fusions in clinical practice, this issues contributes to generate an incomplete molecular profile for the NSCLC patients. 4 For all these reason, the aim of this project is to validate the possibility to detect clinically relevant gene fusions in advanced NSCLC patients by adopting next generation sequencing (NGS) platform starting from RNA extracted from different specimens; secondary aim is the evaluation of the concordance rate between the two different NGS gene panels on RNA samples and an orthogonal platform with the same reference range. Results will be compared with those obtained from RNA extracted on corresponding tissue specimens for each patient analyzed by a validated customized multiplex panel on nCounter platform (Nanostring Technologies, Seattle, WA), in Pangaea institute.

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