Plasma Based Protein Signatures Associated with Small Cell Lung Cancer

SIMPLE SUMMARY: Small-cell lung cancer (SCLC) typically presents at an advanced stage and is associated with high mortality. When diagnosed at an early stage with localized disease, long-term survival can, however, be achieved. In this study, we report a comprehensive proteomic profiling of case plasmas collected at the time of diagnosis or preceding diagnosis of SCLC with the objective of identifying blood-based markers associated with disease pathogenesis. Our study reveals the occurrence of circulating protein features centered on signatures of oncogenic MYC and YAP1 that were elevated in plasmas of cases at and before the time-of-diagnosis of SCLC. We further report several proteins, particularly inflammatory markers, that were identified as elevated in plasma several years prior to the diagnosis of SCLC and that may indicate increased risk of disease. In summary, our study identifies several novel circulating proteins associated with SCLC development that may offer utility for early detection. ABSTRACT: Small-cell-lung cancer (SCLC) is associated with overexpression of oncogenes including Myc family genes and YAP1 and inactivation of tumor suppressor genes. We performed in-depth proteomic profiling of plasmas collected from 15 individuals with newly diagnosed early stage SCLC and from 15 individuals before the diagnosis of SCLC and compared findings with plasma proteomic profiles of 30 matched controls to determine the occurrence of signatures that reflect disease pathogenesis. A total of 272 proteins were elevated (area under the receiver operating characteristic curve (AUC) ≥ 0.60) among newly diagnosed cases compared to matched controls of which 31 proteins were also elevated (AUC ≥ 0.60) in case plasmas collected within one year prior to diagnosis. Ingenuity Pathway analyses of SCLC-associated proteins revealed enrichment of signatures of oncogenic MYC and YAP1. Intersection of proteins elevated in case plasmas with proteomic profiles of conditioned medium from 17 SCLC cell lines yielded 52 overlapping proteins characterized by YAP1-associated signatures of cytoskeletal re-arrangement and epithelial-to-mesenchymal transition. Among samples collected more than one year prior to diagnosis there was a predominance of inflammatory markers. Our integrated analyses identified novel circulating protein features in early stage SCLC associated with oncogenic drivers.