Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma
Abstract Endometrial carcinoma (EC) is the most common gynecological malignancy and fibroblast growth factor receptor 2 (FGFR2) is a frequently dysregulated receptor tyrosine kinase. FGFR2b and FGFR2c are the two main splice isoforms of FGFR2 and are normally localized in epithelial and mesenchymal...
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| Format: | Article |
| Language: | English |
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Wiley
2022-11-01
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| Series: | The Journal of Pathology: Clinical Research |
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| Online Access: | https://doi.org/10.1002/cjp2.286 |
| _version_ | 1817968433038360576 |
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| author | Asmerom T Sengal Deborah Smith Cameron E Snell Samuel Leung Aline Talhouk Elizabeth D Williams Jessica N McAlpine Pamela M Pollock |
| author_facet | Asmerom T Sengal Deborah Smith Cameron E Snell Samuel Leung Aline Talhouk Elizabeth D Williams Jessica N McAlpine Pamela M Pollock |
| author_sort | Asmerom T Sengal |
| collection | DOAJ |
| description | Abstract Endometrial carcinoma (EC) is the most common gynecological malignancy and fibroblast growth factor receptor 2 (FGFR2) is a frequently dysregulated receptor tyrosine kinase. FGFR2b and FGFR2c are the two main splice isoforms of FGFR2 and are normally localized in epithelial and mesenchymal cells, respectively. Previously, we demonstrated that FGFR2c mRNA expression was associated with aggressive tumor characteristics, shorter progression‐free survival (PFS), and disease‐specific survival (DSS) in endometrioid ECs (EECs). The objectives of this study were to investigate the spatial expression of FGFR2b in normal and hyperplasia with and without atypia of human endometrium and to assess the prognostic significance of FGFR2b expression in EC. FGFR2b and FGFR2c mRNA expression was evaluated in normal (proliferative [n = 10], secretory [n = 15], and atrophic [n = 10] endometrium), hyperplasia with and without atypia (n = 19) as well as two patient cohorts of EC samples (discovery [n = 78] and Vancouver [n = 460]) using isoform‐specific BaseScope RNA in situ hybridization assays. Tumors were categorized based on FGFR2 isoform expression (one, both, or neither) and categories were correlated with clinicopathologic markers, molecular subtypes, and clinical outcomes. The FGFR2b splice isoform was exclusively expressed in the epithelial compartment of normal endometrium and hyperplasia without atypia. We observed FGFR2c expression at the basalis layer of glands in 33% (3/9) of hyperplasia with atypia. In patients with EEC, FGFR2b+/FGFR2c− expression was found in 48% of the discovery cohort and 35% of the validation Vancouver cohort. In univariate analyses, tumors with FGFR2b+/FGFR2c− expression had longer PFS (hazard ratio [HR] 0.265; 95% CI 0.145–0.423; log‐rank p < 0.019) and DSS (HR 0.31; 95% CI 0.149–0.622; log‐rank p < 0.001) compared to tumors with FGFR2b−/FGFR2c+ expression in the large EEC Vancouver cohort. In multivariable Cox regression analyses, tumors with FGFR2b+/FGFR2c− expression were significantly associated with longer DSS (HR 0.37; 95% CI 0.153–0.872; log‐rank p < 0.023) compared to FGFR2b−/FGFR2c+ tumors. In conclusion, FGFR2b+/FGFR2c− expression is associated with favorable clinicopathologic markers and clinical outcomes suggesting that FGFR2b could play a role in tailoring the management of EEC patients in the clinic if these findings are confirmed in an independent cohort. |
| first_indexed | 2024-04-13T20:07:40Z |
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| institution | Directory Open Access Journal |
| issn | 2056-4538 |
| language | English |
| last_indexed | 2024-04-13T20:07:40Z |
| publishDate | 2022-11-01 |
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| series | The Journal of Pathology: Clinical Research |
| spelling | doaj.art-4847d837df14472782a00eb999c1ccf32022-12-22T02:31:56ZengWileyThe Journal of Pathology: Clinical Research2056-45382022-11-018652153710.1002/cjp2.286Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinomaAsmerom T Sengal0Deborah Smith1Cameron E Snell2Samuel Leung3Aline Talhouk4Elizabeth D Williams5Jessica N McAlpine6Pamela M Pollock7School of Biomedical Sciences, Faculty of Health Queensland University of Technology (QUT) located at the Translational Research Institute (TRI) Brisbane AustraliaMater Pathology Mater Research and University of Queensland Brisbane AustraliaMater Pathology Mater Research and University of Queensland Brisbane AustraliaDepartment of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre University of British Columbia Vancouver BC CanadaDepartment of Gynaecology and Obstetrics, Division of Gynaecologic Oncology University of British Columbia Vancouver BC CanadaSchool of Biomedical Sciences, Faculty of Health Queensland University of Technology (QUT) located at the Translational Research Institute (TRI) Brisbane AustraliaDepartment of Gynaecology and Obstetrics, Division of Gynaecologic Oncology University of British Columbia Vancouver BC CanadaSchool of Biomedical Sciences, Faculty of Health Queensland University of Technology (QUT) located at the Translational Research Institute (TRI) Brisbane AustraliaAbstract Endometrial carcinoma (EC) is the most common gynecological malignancy and fibroblast growth factor receptor 2 (FGFR2) is a frequently dysregulated receptor tyrosine kinase. FGFR2b and FGFR2c are the two main splice isoforms of FGFR2 and are normally localized in epithelial and mesenchymal cells, respectively. Previously, we demonstrated that FGFR2c mRNA expression was associated with aggressive tumor characteristics, shorter progression‐free survival (PFS), and disease‐specific survival (DSS) in endometrioid ECs (EECs). The objectives of this study were to investigate the spatial expression of FGFR2b in normal and hyperplasia with and without atypia of human endometrium and to assess the prognostic significance of FGFR2b expression in EC. FGFR2b and FGFR2c mRNA expression was evaluated in normal (proliferative [n = 10], secretory [n = 15], and atrophic [n = 10] endometrium), hyperplasia with and without atypia (n = 19) as well as two patient cohorts of EC samples (discovery [n = 78] and Vancouver [n = 460]) using isoform‐specific BaseScope RNA in situ hybridization assays. Tumors were categorized based on FGFR2 isoform expression (one, both, or neither) and categories were correlated with clinicopathologic markers, molecular subtypes, and clinical outcomes. The FGFR2b splice isoform was exclusively expressed in the epithelial compartment of normal endometrium and hyperplasia without atypia. We observed FGFR2c expression at the basalis layer of glands in 33% (3/9) of hyperplasia with atypia. In patients with EEC, FGFR2b+/FGFR2c− expression was found in 48% of the discovery cohort and 35% of the validation Vancouver cohort. In univariate analyses, tumors with FGFR2b+/FGFR2c− expression had longer PFS (hazard ratio [HR] 0.265; 95% CI 0.145–0.423; log‐rank p < 0.019) and DSS (HR 0.31; 95% CI 0.149–0.622; log‐rank p < 0.001) compared to tumors with FGFR2b−/FGFR2c+ expression in the large EEC Vancouver cohort. In multivariable Cox regression analyses, tumors with FGFR2b+/FGFR2c− expression were significantly associated with longer DSS (HR 0.37; 95% CI 0.153–0.872; log‐rank p < 0.023) compared to FGFR2b−/FGFR2c+ tumors. In conclusion, FGFR2b+/FGFR2c− expression is associated with favorable clinicopathologic markers and clinical outcomes suggesting that FGFR2b could play a role in tailoring the management of EEC patients in the clinic if these findings are confirmed in an independent cohort.https://doi.org/10.1002/cjp2.286alternative splicingbiomarkersendometrial carcinomauterine cancerendometrial hyperplasiaFGFR2b isoform |
| spellingShingle | Asmerom T Sengal Deborah Smith Cameron E Snell Samuel Leung Aline Talhouk Elizabeth D Williams Jessica N McAlpine Pamela M Pollock Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma The Journal of Pathology: Clinical Research alternative splicing biomarkers endometrial carcinoma uterine cancer endometrial hyperplasia FGFR2b isoform |
| title | Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma |
| title_full | Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma |
| title_fullStr | Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma |
| title_full_unstemmed | Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma |
| title_short | Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma |
| title_sort | spatial expression of the fgfr2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma |
| topic | alternative splicing biomarkers endometrial carcinoma uterine cancer endometrial hyperplasia FGFR2b isoform |
| url | https://doi.org/10.1002/cjp2.286 |
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