Assessing expression patterns of PTGR1, a potential biomarker for acylfulven sensitivity in urothelial carcinoma
Abstract Background Metastatic urothelial carcinoma (mUC) has a poor prognosis, despite recent therapeutic advancements. Prostaglandin Reductase 1 (PTGR1) is essential for activating acylfulvens, a promising class of drugs for treating a subset of urothelial carcinoma (UC) patients. The efficacy of...
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Nature Portfolio
2024-11-01
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| author | Dag Rune Stormoen Signe Lehn Kent W. Mouw Zoltan Szallasi Linea Cecilie Melchior Line Hammer Dohn Judit Börcsok Maria Rossing Birgitte Grønkaer Toft Helle Pappot |
| author_facet | Dag Rune Stormoen Signe Lehn Kent W. Mouw Zoltan Szallasi Linea Cecilie Melchior Line Hammer Dohn Judit Börcsok Maria Rossing Birgitte Grønkaer Toft Helle Pappot |
| author_sort | Dag Rune Stormoen |
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| description | Abstract Background Metastatic urothelial carcinoma (mUC) has a poor prognosis, despite recent therapeutic advancements. Prostaglandin Reductase 1 (PTGR1) is essential for activating acylfulvens, a promising class of drugs for treating a subset of urothelial carcinoma (UC) patients. The efficacy of acylfulvens depends on PTGR1 activity and defects in the nucleotide excision repair (NER) pathway, notably ERCC2 mutations present in 10–15% of bladder tumors. This study identifies patients eligible to be included in acylfulven clinical trials based on the presence of PTGR-1 by immunohistochemistry (IHC) staining, RNA expression level and mutations in the NER pathway. Additionally, it evaluates PTGR-1 expression as a prognostic biomarker. Methods Three PTGR-1 antibodies were tested in a kidney cancer cell line A498 and in tissues with known PTGR1 expression (liver, tonsils, pancreas, small intestine, etc.). Patients with untreated mUC receiving 1st line platinum from Dec. 2019 to Dec. 2021 in the Capital Region, Denmark, were included retrospectively. FFPE tumor samples were collected, and tissue microarrays (TMAs) were constructed. TMAs were stained with the best-performing PTGR1 antibody, RNA expression was analyzed using Nanostring nCounter PanCancer panel and gene mutations were assessed using a targeted genomic panel (TSO-500). Kaplan-Meier and multivariate Cox regression assessed overall survival and covariate impacts. Results The AB181131 PTGR1 antibody was the most reliable in validation tissues. Tumors from 71 mUC patients were used to construct the TMA, and 40% of tumors scored positive for PTGR1 by IHC staining. A normalized PTGR1 RNA cutoff at 2,550 normalized counts achieved an AUC of 0.9, defining 35 samples as positive with a sensitivity of 96% and specificity of 85% in relation to IHC-positivity. Differential expression showed a significant upregulation of PTGR1 RNA in PTGR1 IHC-positive cases. NER-deficiency and PTGR1 positivity (mutations in ERCC1, ERCC2, ERCC3, ERCC4) was seen in 9 patients (13%). Median overall survival was 16 months in the cohort. Overall survival (OS) analysis indicates that overexpression of PTGR1 RNA was associated with a reduced median OS (12 months vs. 25 months, p = 0.039, log-rank). Conclusion PTGR1 IHC staining pattern using the Abcam AB181131 antibody is highly correlated with PTGR1 RNA expression. 13% in our cohort were identified as NER deficient and PTGR1 positive. Lower levels of PTGR1 indicates better outcome in this cohort. |
| format | Article |
| id | doaj-art-cbe03a455d9d4cd08c3d82aaa8d9d930 |
| institution | Kabale University |
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| publishDate | 2024-11-01 |
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| spelling | doaj-art-cbe03a455d9d4cd08c3d82aaa8d9d9302024-11-10T12:17:04ZengNature PortfolioScientific Reports2045-23222024-11-0114111110.1038/s41598-024-79334-xAssessing expression patterns of PTGR1, a potential biomarker for acylfulven sensitivity in urothelial carcinomaDag Rune Stormoen0Signe Lehn1Kent W. Mouw2Zoltan Szallasi3Linea Cecilie Melchior4Line Hammer Dohn5Judit Börcsok6Maria Rossing7Birgitte Grønkaer Toft8Helle Pappot9Department of Oncology, Copenhagen University HospitalDepartment of Pathology, Copenhagen University HospitalDepartment of Radiation Oncology, Dana Farber Cancer Institute, Brigham and Women’s HospitalHarvard Medical SchoolDepartment of Pathology, Copenhagen University HospitalDepartment of Oncology, Copenhagen University HospitalTranslational Cancer Genomics Group, Danish Cancer InstituteDepartment of Clinical Medicine, Copenhagen UniversityDepartment of Pathology, Copenhagen University HospitalDepartment of Oncology, Copenhagen University HospitalAbstract Background Metastatic urothelial carcinoma (mUC) has a poor prognosis, despite recent therapeutic advancements. Prostaglandin Reductase 1 (PTGR1) is essential for activating acylfulvens, a promising class of drugs for treating a subset of urothelial carcinoma (UC) patients. The efficacy of acylfulvens depends on PTGR1 activity and defects in the nucleotide excision repair (NER) pathway, notably ERCC2 mutations present in 10–15% of bladder tumors. This study identifies patients eligible to be included in acylfulven clinical trials based on the presence of PTGR-1 by immunohistochemistry (IHC) staining, RNA expression level and mutations in the NER pathway. Additionally, it evaluates PTGR-1 expression as a prognostic biomarker. Methods Three PTGR-1 antibodies were tested in a kidney cancer cell line A498 and in tissues with known PTGR1 expression (liver, tonsils, pancreas, small intestine, etc.). Patients with untreated mUC receiving 1st line platinum from Dec. 2019 to Dec. 2021 in the Capital Region, Denmark, were included retrospectively. FFPE tumor samples were collected, and tissue microarrays (TMAs) were constructed. TMAs were stained with the best-performing PTGR1 antibody, RNA expression was analyzed using Nanostring nCounter PanCancer panel and gene mutations were assessed using a targeted genomic panel (TSO-500). Kaplan-Meier and multivariate Cox regression assessed overall survival and covariate impacts. Results The AB181131 PTGR1 antibody was the most reliable in validation tissues. Tumors from 71 mUC patients were used to construct the TMA, and 40% of tumors scored positive for PTGR1 by IHC staining. A normalized PTGR1 RNA cutoff at 2,550 normalized counts achieved an AUC of 0.9, defining 35 samples as positive with a sensitivity of 96% and specificity of 85% in relation to IHC-positivity. Differential expression showed a significant upregulation of PTGR1 RNA in PTGR1 IHC-positive cases. NER-deficiency and PTGR1 positivity (mutations in ERCC1, ERCC2, ERCC3, ERCC4) was seen in 9 patients (13%). Median overall survival was 16 months in the cohort. Overall survival (OS) analysis indicates that overexpression of PTGR1 RNA was associated with a reduced median OS (12 months vs. 25 months, p = 0.039, log-rank). Conclusion PTGR1 IHC staining pattern using the Abcam AB181131 antibody is highly correlated with PTGR1 RNA expression. 13% in our cohort were identified as NER deficient and PTGR1 positive. Lower levels of PTGR1 indicates better outcome in this cohort.https://doi.org/10.1038/s41598-024-79334-xBladder cancerUrothelial cancerBiomarkerValidation studyDNA repair deficiencyPTGR1 |
| spellingShingle | Dag Rune Stormoen Signe Lehn Kent W. Mouw Zoltan Szallasi Linea Cecilie Melchior Line Hammer Dohn Judit Börcsok Maria Rossing Birgitte Grønkaer Toft Helle Pappot Assessing expression patterns of PTGR1, a potential biomarker for acylfulven sensitivity in urothelial carcinoma Scientific Reports Bladder cancer Urothelial cancer Biomarker Validation study DNA repair deficiency PTGR1 |
| title | Assessing expression patterns of PTGR1, a potential biomarker for acylfulven sensitivity in urothelial carcinoma |
| title_full | Assessing expression patterns of PTGR1, a potential biomarker for acylfulven sensitivity in urothelial carcinoma |
| title_fullStr | Assessing expression patterns of PTGR1, a potential biomarker for acylfulven sensitivity in urothelial carcinoma |
| title_full_unstemmed | Assessing expression patterns of PTGR1, a potential biomarker for acylfulven sensitivity in urothelial carcinoma |
| title_short | Assessing expression patterns of PTGR1, a potential biomarker for acylfulven sensitivity in urothelial carcinoma |
| title_sort | assessing expression patterns of ptgr1 a potential biomarker for acylfulven sensitivity in urothelial carcinoma |
| topic | Bladder cancer Urothelial cancer Biomarker Validation study DNA repair deficiency PTGR1 |
| url | https://doi.org/10.1038/s41598-024-79334-x |
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