Urinary DNA-methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer-free individuals
Abstract Background For more than 80 years, cystoscopy has been the gold standard for identification of urothelial carcinoma (UCa). Because of many factors, such as pain of the patients during this procedure or the costs involved, non-invasive detection of UCa remains a challenge. Herein, we verify...
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2024-11-01
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| Online Access: | https://doi.org/10.1186/s12967-024-05844-x |
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| author | Kerstin Lang Christina U. Köhler Katharina Wichert Thomas Deix Georg Bartsch Gudrun Sommer Christiane Lübke Florian Roghmann Moritz J. Reike Harald Krentel Katja Engellandt Sven Schiermeier Valentin Menke Joachim Noldus Thomas Behrens Thomas Brüning Heiko U. Käfferlein |
| author_facet | Kerstin Lang Christina U. Köhler Katharina Wichert Thomas Deix Georg Bartsch Gudrun Sommer Christiane Lübke Florian Roghmann Moritz J. Reike Harald Krentel Katja Engellandt Sven Schiermeier Valentin Menke Joachim Noldus Thomas Behrens Thomas Brüning Heiko U. Käfferlein |
| author_sort | Kerstin Lang |
| collection | DOAJ |
| description | Abstract Background For more than 80 years, cystoscopy has been the gold standard for identification of urothelial carcinoma (UCa). Because of many factors, such as pain of the patients during this procedure or the costs involved, non-invasive detection of UCa remains a challenge. Herein, we verify our previously identified urinary biomarkers C-X-C Motif Chemokine Ligand 16 (CXCL16) and transforming growth-factor beta induced protein (TGFBI) on the protein level as well as the CpG sites ALOX5, TRPS1 and an intergenic region on Chromosome 16 on DNA methylation level in an independent cross-sectional study. Methods We collected N = 1119 urines from individuals coming to urological and gynecological check-ups, follow-up care or patients suspicious for UCa or already diagnosed for different urologic or gynecologic cancer entities. We performed methylation analysis of various CpG sites with DNA isolated from urine sediment and quantified the concentration of the protein markers CXCL16 and TGFBI in the corresponding urine supernatant using ELISA. We tested for patient-group differences with two-sided Wilcoxon rank sum tests and examined the performance with receiver operating characteristic curves. For verification, we analyzed the marker performance with previously set cutoff-values and marker combinations with established and experimental algorithms (with logical OR-conjunction, iterative threshold-based biomarker and score combining algorithm “PanelomiX”). Results Evaluation confirmed that our previously identified protein and DNA methylation biomarkers can distinguish UCa from frequent urological and gynecological cancers. CXCL16 and TGFBI discriminated UCa cases with a sensitivity of 31% and 56% and a specificity of 94% and 85%, respectively. Combining methylation markers resulted in UCa detection in men with a sensitivity of 54% and a specificity of 94%. Extending analysis by combining all methylation and protein markers (up to five markers in total) yielded a convincingly high specificity of 97% at a sensitivity of 72% for the identification of UCa patients within a heterogeneous collective of cancer-free individuals and patients suffering from urological or gynecological cancers. Conclusion Combining various biomarkers at protein and DNA level demonstrates a new option of non-invasive UCa diagnosis in urine, and thus might help to reduce the number of unnecessary cystoscopies, especially in patients without a history of UCa. |
| format | Article |
| id | doaj-art-41b44147a5364a0ab27d2909476f4645 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-41b44147a5364a0ab27d2909476f46452024-12-01T12:42:36ZengBMCJournal of Translational Medicine1479-58762024-11-0122111610.1186/s12967-024-05844-xUrinary DNA-methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer-free individualsKerstin Lang0Christina U. Köhler1Katharina Wichert2Thomas Deix3Georg Bartsch4Gudrun Sommer5Christiane Lübke6Florian Roghmann7Moritz J. Reike8Harald Krentel9Katja Engellandt10Sven Schiermeier11Valentin Menke12Joachim Noldus13Thomas Behrens14Thomas Brüning15Heiko U. Käfferlein16Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA)Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA)Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA)URO DR, Clinic of Urology and AndrologyURO DR, Clinic of Urology and AndrologySurgery of GynecologySurgery of GynecologyDepartment of Urology, Marien Hospital Herne, Ruhr University BochumDepartment of Urology, Marien Hospital Herne, Ruhr University BochumDepartment of Obstetrics and Gynecology, Bethesda HospitalDepartment of Obstetrics and Gynecology, Bethesda HospitalDepartment of Obstetrics and Gynecology, Marien-Hospital, University Witten-HerdeckeDepartment of Obstetrics and Gynecology, St. Anna HospitalDepartment of Urology, Marien Hospital Herne, Ruhr University BochumInstitute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA)Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA)Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA)Abstract Background For more than 80 years, cystoscopy has been the gold standard for identification of urothelial carcinoma (UCa). Because of many factors, such as pain of the patients during this procedure or the costs involved, non-invasive detection of UCa remains a challenge. Herein, we verify our previously identified urinary biomarkers C-X-C Motif Chemokine Ligand 16 (CXCL16) and transforming growth-factor beta induced protein (TGFBI) on the protein level as well as the CpG sites ALOX5, TRPS1 and an intergenic region on Chromosome 16 on DNA methylation level in an independent cross-sectional study. Methods We collected N = 1119 urines from individuals coming to urological and gynecological check-ups, follow-up care or patients suspicious for UCa or already diagnosed for different urologic or gynecologic cancer entities. We performed methylation analysis of various CpG sites with DNA isolated from urine sediment and quantified the concentration of the protein markers CXCL16 and TGFBI in the corresponding urine supernatant using ELISA. We tested for patient-group differences with two-sided Wilcoxon rank sum tests and examined the performance with receiver operating characteristic curves. For verification, we analyzed the marker performance with previously set cutoff-values and marker combinations with established and experimental algorithms (with logical OR-conjunction, iterative threshold-based biomarker and score combining algorithm “PanelomiX”). Results Evaluation confirmed that our previously identified protein and DNA methylation biomarkers can distinguish UCa from frequent urological and gynecological cancers. CXCL16 and TGFBI discriminated UCa cases with a sensitivity of 31% and 56% and a specificity of 94% and 85%, respectively. Combining methylation markers resulted in UCa detection in men with a sensitivity of 54% and a specificity of 94%. Extending analysis by combining all methylation and protein markers (up to five markers in total) yielded a convincingly high specificity of 97% at a sensitivity of 72% for the identification of UCa patients within a heterogeneous collective of cancer-free individuals and patients suffering from urological or gynecological cancers. Conclusion Combining various biomarkers at protein and DNA level demonstrates a new option of non-invasive UCa diagnosis in urine, and thus might help to reduce the number of unnecessary cystoscopies, especially in patients without a history of UCa.https://doi.org/10.1186/s12967-024-05844-xBladder cancerVerificationUrineBiomarkersDNA methylation |
| spellingShingle | Kerstin Lang Christina U. Köhler Katharina Wichert Thomas Deix Georg Bartsch Gudrun Sommer Christiane Lübke Florian Roghmann Moritz J. Reike Harald Krentel Katja Engellandt Sven Schiermeier Valentin Menke Joachim Noldus Thomas Behrens Thomas Brüning Heiko U. Käfferlein Urinary DNA-methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer-free individuals Journal of Translational Medicine Bladder cancer Verification Urine Biomarkers DNA methylation |
| title | Urinary DNA-methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer-free individuals |
| title_full | Urinary DNA-methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer-free individuals |
| title_fullStr | Urinary DNA-methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer-free individuals |
| title_full_unstemmed | Urinary DNA-methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer-free individuals |
| title_short | Urinary DNA-methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer-free individuals |
| title_sort | urinary dna methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer free individuals |
| topic | Bladder cancer Verification Urine Biomarkers DNA methylation |
| url | https://doi.org/10.1186/s12967-024-05844-x |
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