Towards natural isotopic variations in the cancer omics landscape

Cancer is a heterogeneous disease that remains incompletely understood, with its complexities yet to be fully integrated into a comprehensive framework that includes biomarkers supporting personalized approaches. Advances in omics technologies have improved our understanding of cancer, paving the way for more personalized treatments. However, current omics primarily focus on changes in the levels of metabolites, proteins, lipids, and nucleic acids, and additional insight into metabolism typically requires coupling to isotopically enriched tracers. Here, we introduce an emerging approach with significant potential to enhance cancer omics: natural isotopic variations. We review documented changes in natural isotopic abundances in cancerous tissues to identify trends and their implications, and demonstrate potential at both the in vitro and whole-body levels. Technological advancements in mass spectrometry hold great promise for obtaining isotopic data during traditional omics analyses, paving the way for a more comprehensive approach to cancer biomarker discovery. This review highlights the potential of natural isotopic variations to broaden the scope of cancer omics. • Cancer induces natural isotopic variations that can expand the scope of omics analyses. • Natural isotope ratios provide insights at tumor, whole-body, and in vitro model levels. • Advances in mass spectrometry enable simultaneous acquisition of natural isotopic and traditional omics data.