Shared Plasma Fatty Acid Profiles in Four Cancer Types Enable Diagnosis and Discrimination of Gastrointestinal and Lung Cancers

<b>Background:</b> Cancer is a leading cause of mortality worldwide, characterized by metabolic reprogramming, including alterations in fatty acid (FA) metabolism. Plasma FA profiles hold promise as non-invasive biomarkers for the diagnosis and classification of cancer. <b>Objectives:</b> This study aimed to investigate the diagnostic potential of plasma FA profiles across four major cancers and to identify shared and cancer-type-specific metabolic alterations. <b>Methods:</b> We examine comprehensive FA profiling of plasma samples from 368 individuals, including patients with colorectal (CRC, n = 94), gastric (GC, n = 55), esophageal (EC, n = 53), and lung cancer (LC, n = 73), alongside 93 healthy controls (HCs) by gas chromatography-mass spectrometry. Data were analyzed using univariate statistics and multivariate modeling analysis. <b>Results:</b> Univariate analysis showed a shared set of altered FAs across the cancer types, demonstrating a shared pan-cancer metabolic shift. A comprehensive comparison revealed a remarkable shared pattern within the gastrointestinal (GI) cancers (GC, CRC, EC), while LC showed opposite trends for most FAs. Partial Least Squares Discriminant Analysis (PLS-DA) models on a 70% training set excellently discriminated each cancer type from HCs. The cross-validation of the model demonstrated robust internal performance with Q² = 0.675 (LC), 0.559 (GC), 0.774 (CRC), and 0.628 (EC). This is followed by assessing the diagnostic accuracy on a 30% hold-out test set, with area under the curve (AUC) values of 0.686 (LC), 0.926 (GC), 0.905 (CRC), and 0.843 (EC). <b>Conclusions:</b> Plasma FA profiles may provide a potential source of biomarkers, capturing both shared cancer markers and distinct tissue-specific metabolic alterations. These findings highlight the high diagnostic and classificatory potential of FAs alterations in oncology.