A Blood-Based Proteomic Classifier for the Molecular Characterization of Pulmonary Nodules

Abstract

Each year millions of pulmonary nodules are discovered by computed tomography and subsequently biopsied. As the majority of these nodules are benign, many patients undergo unnecessary and costly invasive procedures. We present a 13-protein blood-based classifier that differentiates malignant and benign nodules with high confidence, thereby providing a diagnostic tool to avoid invasive biopsy on benign nodules. Using a systems biology strategy, 371 protein candidates were identified and a multiple reaction monitoring (MRM) assay was developed for each. The MRM assays were applied in a three-site discovery study (n = 143) on plasma samples from patients with benign and Stage IA cancer matched on nodule size, age, gender and clinical site, producing a 13-protein classifier. The classifier was validated on an independent set of plasma samples (n = 104), exhibiting a high negative predictive value (NPV) of 90%. Validation performance on samples from a non-discovery clinical site showed NPV of 94%, indicating the general effectiveness of the classifier. A pathway analysis demonstrated that the classifier proteins are likely modulated by a few transcription regulators (NF2L2, AHR, MYC, FOS) that are associated with lung cancer, lung inflammation and oxidative stress networks. The classifier score was independent of patient nodule size, smoking history and age, which are risk factors used for clinical management of pulmonary nodules. Thus this molecular test can provide a powerful complementary tool for physicians in lung cancer diagnosis.

The P4 Health Spectrum – A Predictive, Preventive, Personalized and Participatory Continuum for Promoting Healthspan

“…118 However, for many diseases (including cancer), clinically useful biomarkers are just beginning to appear and are not yet wide spread. 119,120 For example, a 13 protein blood panel that has the ability to distinguish benign from neoplastic lung nodules has recently been developed; this simple expediency can save the healthcare system $3.5 billion a year in avoiding unnecessary surgeries. This is now an available CLIA approved test.…”

“…This is now an available CLIA approved test. 120 Future systems biology research will help to discover new biomolecular networks and biomarkers for disease prediction and monitoring. Biomarkers of pharmacogenomics and targets will also be of interest to improve bio-pharmaceutical interventions.…”

Emerging Proteomic Technologies Provide Enormous and Underutilized Potential for Brain Cancer Research

“…Let us take the example of the clinically available lung cancer marker panel based on mass spectrometry proteomics as an illustrative example of how targeted proteomics could be used to develop blood-based biomarkers for brain cancers as well (2). The strategy for developing this panel began with a set of about 400 candidates selected based on their biological relevance to the cancer and their likelihood of being found in the blood.…”

“…One then asked which proteins were "cooperative" in that they were most frequently found in the higher scoring panels. A final panel of the best performing proteins from this highly "cooperative" set resulted in a 13-marker panel (2). A classifier based on this panel was trained from data obtained at three independent sites, and the validation stage proceeded not only at these three sites with new independent samples, but, importantly, also at a fourth site that had no involvement in the discovery phase.…”

“…These advances span areas such as single cell proteomics, targeted proteomics via mass spectrometry (MS) (the Nature method of the year in 2012 (1)), profiling of post translational modifications (PTMs), and large-scale protein screening chips based on modified aptamers and Elisa assays. Multiparameter proteomics approaches have also been recently adopted in the clinic (2). In this brief perspective, we discuss a number of the latest advances in proteomics and their implications for brain cancer research going forward.…”