PURPOSE: RCC, the most common type of kidney cancer, is associated with high mortality. A non-invasive diagnostic test remains unavailable due to the lack of RCC-specific biomarkers in body fluids. We have previously described a significantly altered profile of sulfatides in RCC tumor tissues, motivating us to investigate whether these alterations are reflected in collectible body fluids and whether they can enable RCC detection. METHODS: We collected and further analyzed 143 plasma, 100 urine, and 154 tissue samples from 155 kidney cancer patients, together with 207 plasma and 70 urine samples from 214 healthy controls. RESULTS: For the first time, we show elevated concentrations of lactosylsulfatides and decreased levels of sulfatides with hydroxylated fatty acyls in body fluids of RCC patients compared to controls. These alterations are emphasized in patients with the advanced tumor stage. Classification models are able to distinguish between controls and patients with RCC. In the case of all plasma samples, the AUC for the testing set was 0.903 (0.844-0.954), while for urine samples it was 0.867 (0.763-0.953). The models are able to efficiently detect patients with early- and late-stage RCC based on plasma samples as well. The test set sensitivities were 80.6% and 90%, and AUC values were 0.899 (0.832-0.952) and 0.981 (0.956-0.998), respectively. CONCLUSION: Similar trends in body fluids and tissues indicate that RCC influences lipid metabolism, and highlight the potential of the studied lipids for minimally-invasive cancer detection, including patients with early tumor stages, as demonstrated by the predictive ability of the applied classification models.

• Keywords
• cancer biomarkers, classification models, early detection, lipidomics, renal cell carcinoma, sphingomyelins, sulfatide,
• Publication type
• Journal Article MeSH

Early detection of cancer is one of the unmet needs in clinical medicine. Peripheral blood analysis is a preferred method for efficient population screening, because blood collection is well embedded in clinical practice and minimally invasive for patients. Lipids are important biomolecules, and variations in lipid concentrations can reflect pathological disorders. Lipidomic profiling of human plasma by the coupling of ultrahigh-performance supercritical fluid chromatography and mass spectrometry is investigated with the aim to distinguish patients with breast, kidney, and prostate cancers from healthy controls. The mean sensitivity, specificity, and accuracy of the lipid profiling approach were 85%, 95%, and 92% for kidney cancer; 91%, 97%, and 94% for breast cancer; and 87%, 95%, and 92% for prostate cancer. No association of statistical models with tumor stage is observed. The statistically most significant lipid species for the differentiation of cancer types studied are CE 16:0, Cer 42:1, LPC 18:2, PC 36:2, PC 36:3, SM 32:1, and SM 41:1 These seven lipids represent a potential biomarker panel for kidney, breast, and prostate cancer screening, but a further verification step in a prospective study has to be performed to verify clinical utility.

• MeSH
• Early Detection of Cancer MeSH
• Adult MeSH
• Heparin chemistry   MeSH
• Mass Spectrometry MeSH
• Kidney metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipidomics * MeSH
• Lipids chemistry   MeSH
• Young Adult MeSH
• Biomarkers, Tumor metabolism   MeSH
• Prostatic Neoplasms metabolism   MeSH
• Breast Neoplasms metabolism   MeSH
• Area Under Curve MeSH
• Prospective Studies MeSH
• Prostate metabolism   MeSH
• Breast metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Reproducibility of Results MeSH
• Retrospective Studies MeSH
• ROC Curve MeSH
• Aged MeSH
• Models, Statistical MeSH
• Case-Control Studies MeSH
• Chromatography, Supercritical Fluid MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Heparin MeSH
• Lipids MeSH
• Biomarkers, Tumor MeSH

Matrix-assisted laser desorption/ionization coupled with Orbitrap mass spectrometry (MALDI-Orbitrap-MS) is used for the clinical study of patients with renal cell carcinoma (RCC), as the most common type of kidney cancer. Significant changes in sulfoglycosphingolipid abundances between tumor and autologous normal kidney tissues are observed. First, sulfoglycosphingolipid species in studied RCC samples are identified using high mass accuracy full scan and tandem mass spectra. Subsequently, optimization, method validation, and statistical evaluation of MALDI-MS data for 158 tissues of 80 patients are discussed. More than 120 sulfoglycosphingolipids containing one to five hexosyl units are identified in human RCC samples based on the systematic study of their fragmentation behavior. Many of them are recorded here for the first time. Multivariate data analysis (MDA) methods, i.e., unsupervised principal component analysis (PCA) and supervised orthogonal partial least square discriminant analysis (OPLS-DA), are used for the visualization of differences between normal and tumor samples to reveal the most up- and downregulated lipids in tumor tissues. Obtained results are closely correlated with MALDI mass spectrometry imaging (MSI) and histologic staining. Important steps of the present MALDI-Orbitrap-MS approach are also discussed, such as the selection of best matrix, correct normalization, validation for semiquantitative study, and problems with possible isobaric interferences on closed masses in full scan mass spectra. Graphical Abstract ᅟ.

• Keywords
• MALDI, Orbitrap mass spectrometry, Renal cell carcinoma, Sulfatide, Sulfoglycosphingolipids,
• MeSH
• Principal Component Analysis MeSH
• Carcinoma, Renal Cell chemistry   diagnosis   pathology   MeSH
• Kidney chemistry   pathology   MeSH
• Humans MeSH
• Least-Squares Analysis MeSH
• Multivariate Analysis MeSH
• Biomarkers, Tumor analysis   MeSH
• Kidney Neoplasms chemistry   diagnosis   pathology   MeSH
• Sensitivity and Specificity MeSH
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization methods   MeSH
• Sulfoglycosphingolipids analysis   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Validation Study MeSH
• Names of Substances
• Biomarkers, Tumor MeSH
• Sulfoglycosphingolipids MeSH

Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.

• Keywords
• clinical research, epidemiology, genomics, kidney cancer,
• MeSH
• Biomedical Research MeSH
• Genomics * MeSH
• Humans MeSH
• Kidney Neoplasms etiology   genetics   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH