Circulating biomarkers of kidney tumors in TSC (tuberous sclerosis complex) patients

Patients with tuberous sclerosis complex (TSC) develop an array of multi-organ disease manifestations, with angiomyolipomas (AML) and cysts in the kidneys being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital in lowering TSC patient morbidity and mortality. However, current standard of care for imaging-based methods are not designed for rapid screening, posing challenges for early detection. To identify potential diagnostic screening biomarkers of AML/cysts, we performed global untargeted metabolomics in blood samples from 283 kidney AML/cyst-positive or -negative TSC patients using mass spectrometry. We identified seven highly sensitive chemical features, including octanoic acid, that predict kidney AML/cysts in TSC patients. Patients with elevated octanoic acid have lower levels of very long-chain fatty acids (VLCFAs), suggesting that dysregulated peroxisome activity leads to overproduction of octanoic acid via VLCFA oxidation. This study highlights serum metabolites as novel biomarkers for TSC kidney tumor diagnosis and offers valuable metabolic insights into the disease. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by Department of Defense W81XWH2110254 (to G.L.), National Institutes of Health K22CA234399 (to G. L.), TSC Alliance BSR-01-23 (to G.L.), R01AA029124 (to C.J.), and P30CA062203 (University of California Irvine, Chao Family Comprehensive Cancer Center). J.K. was supported by a postdoctoral fellowship from the TSC Alliance (02-23). C.B.R. was supported by predoctoral fellowship from the University of California Irvine, Interdisciplinary Cancer Research program (T32CA009054). S.J. was supported by a postdoctoral fellowship from the National Research Foundation of Korea (2021R1A6A3A14039681). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of Salus IRB Services (formerly known as Ethical & Independent Review Services) and UC Irvine gave ethical approval for this work. All samples and clinical information were collected in compliance with Salus IRB Services Protocol #15039 (TSC Alliance), UC Irvine IRB Protocol #2012-8716, and UC Irvine IRB Protocol #2021-6823 in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2013. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.