Large, Nested Variant of Urothelial Carcinoma Is Enriched with Activating Mutations in Fibroblast Growth Factor Receptor-3 among Other Targetable Mutations

doi:10.3390/cancers15123167

. 2023 Jun 13;15(12):3167.

doi: 10.3390/cancers15123167.

Large, Nested Variant of Urothelial Carcinoma Is Enriched with Activating Mutations in Fibroblast Growth Factor Receptor-3 among Other Targetable Mutations

Yaser Gamallat^{1

2}, Mitra Afsharpad¹, Soufiane El Hallani³, Christopher A Maher⁴, Nimira Alimohamed⁵, Eric Hyndman⁶, Tarek A Bismar^{1

2

5

7}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
² Department of Oncology, Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
³ Alberta Precision Laboratory, Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R7, Canada.
⁴ Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁵ Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB T2N 4N2, Canada.
⁶ Department of Surgery and Urology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 2T9, Canada.
⁷ Alberta Precision Laboratory, Rockyview General Hospital, Departments of Pathology and Laboratory Medicine, Calgary, AB T2V 1P9, Canada.

PMID: 37370778
PMCID: PMC10296365
DOI: 10.3390/cancers15123167

Large, Nested Variant of Urothelial Carcinoma Is Enriched with Activating Mutations in Fibroblast Growth Factor Receptor-3 among Other Targetable Mutations

Yaser Gamallat et al. Cancers (Basel). 2023.

. 2023 Jun 13;15(12):3167.

doi: 10.3390/cancers15123167.

Authors

Yaser Gamallat^{1

2}, Mitra Afsharpad¹, Soufiane El Hallani³, Christopher A Maher⁴, Nimira Alimohamed⁵, Eric Hyndman⁶, Tarek A Bismar^{1

2

5

7}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
² Department of Oncology, Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
³ Alberta Precision Laboratory, Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R7, Canada.
⁴ Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁵ Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB T2N 4N2, Canada.
⁶ Department of Surgery and Urology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 2T9, Canada.
⁷ Alberta Precision Laboratory, Rockyview General Hospital, Departments of Pathology and Laboratory Medicine, Calgary, AB T2V 1P9, Canada.

PMID: 37370778
PMCID: PMC10296365
DOI: 10.3390/cancers15123167

Abstract

The large, nested variant of urothelial carcinoma (LNVUC) is characterized by bland histomorphology mimicking that of benign von Brunn nests. In the current study, we aimed to investigate the Fibroblast Growth Factor Receptor-3 (FGFR-3) activation and missense mutation in 38 cases, including 6 cases diagnosed with LNVUC and 32 with metastatic invasive urothelial carcinoma (UC). Initially, six formalin-fixed paraffin-embedded (FFPE) tissue samples of the LNVUC were subjected to whole-exome sequencing (WES), and then we performed targeted sequencing on 32 cases of metastatic invasive UC of various morphological subtypes, which were interrogated for the FGFR3. Our results revealed 3/6 (50%) LNVUC cases evaluated by WES in our study showed an activating mutation in FGFR-3, 33% showed an activating mutation in PIK3CA, and 17% showed activating mutation in GNAS or MRE11. Additionally, 33% of cases showed a truncating mutation in CDKN1B. All LNVUC in our study that harbored the FGFR-3 mutation showed additional activating or truncating mutations in other genes. Overall, 6/32 (18.75%) cases of random metastatic invasive UC showed missense mutations of the FGFR-3 gene. The LNVUC variant showed the higher incidence of FGFR-3 mutations compared to other types of mutations. Additionally, all LNVUC cases show additional activating or truncating mutations in other genes, thus being amenable to novel targeted therapy.

Keywords: fibroblast growth factor receptor-3 (FGFR-3); large nested variant of urothelial carcinoma (LNVUC); metastatic urothelial carcinoma; targeted sequencing; whole-exome sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

References

1. Xu N., Yao Z., Shang G., Ye D., Wang H., Zhang H., Qu Y., Xu F., Wang Y., Qin Z., et al. Integrated Proteogenomic Characterization of Urothelial Carcinoma of the Bladder. J. Hematol. Oncol. 2022;15:76. doi: 10.1186/s13045-022-01291-7. - DOI - PMC - PubMed
1. Lobo N., Shariat S., Guo C., Fernandez M., Kassouf W., Choudhury A., Gao J., Williams S., Galsky M., Taylor J.A., 3rd, et al. What is the significance of variant histology in urothelial carcinoma? Eur. Urol. Focus. 2020;6:653–663. doi: 10.1016/j.euf.2019.09.003. - DOI - PubMed
1. Netto G.J., Amin M., Berney D., Comperat E., Gill A., Hartmann A., Menon S., Raspollini M., Rubin M., Srigley J., et al. The 2022 world health organization classification of tumors of the urinary system and male genital organs-part b: Prostate and urinary tract tumors. Eur. Urol. 2022;82:469–482. doi: 10.1016/j.eururo.2022.07.002. - DOI - PubMed
1. Comperat E., McKenney J., Hartmann A., Hes O., Bertz S., Varinot J., Brimo F. Large nested variant of urothelial carcinoma: A clinicopathological study of 36 cases. Histopathology. 2017;71:703–710. doi: 10.1111/his.13280. - DOI - PubMed
1. Weyerer V., Eckstein M., Comperat E., Juette H., Gaisa N., Allory Y., Stohr R., Wullich B., Roupret M., Hartmann A., et al. Pure large nested variant of urothelial carcinoma (lnuc) is the prototype of an fgfr3 mutated aggressive urothelial carcinoma with luminal-papillary phenotype. Cancers. 2020;12:763. doi: 10.3390/cancers12030763. - DOI - PMC - PubMed

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Funding in part was supported by APL resident training grant # RS20-603.

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[1] Xu N., Yao Z., Shang G., Ye D., Wang H., Zhang H., Qu Y., Xu F., Wang Y., Qin Z., et al. Integrated Proteogenomic Characterization of Urothelial Carcinoma of the Bladder. J. Hematol. Oncol. 2022;15:76. doi: 10.1186/s13045-022-01291-7. - DOI - PMC - PubMed

[2] Xu N., Yao Z., Shang G., Ye D., Wang H., Zhang H., Qu Y., Xu F., Wang Y., Qin Z., et al. Integrated Proteogenomic Characterization of Urothelial Carcinoma of the Bladder. J. Hematol. Oncol. 2022;15:76. doi: 10.1186/s13045-022-01291-7. - DOI - PMC - PubMed

[3] Lobo N., Shariat S., Guo C., Fernandez M., Kassouf W., Choudhury A., Gao J., Williams S., Galsky M., Taylor J.A., 3rd, et al. What is the significance of variant histology in urothelial carcinoma? Eur. Urol. Focus. 2020;6:653–663. doi: 10.1016/j.euf.2019.09.003. - DOI - PubMed

[4] Lobo N., Shariat S., Guo C., Fernandez M., Kassouf W., Choudhury A., Gao J., Williams S., Galsky M., Taylor J.A., 3rd, et al. What is the significance of variant histology in urothelial carcinoma? Eur. Urol. Focus. 2020;6:653–663. doi: 10.1016/j.euf.2019.09.003. - DOI - PubMed

[5] Netto G.J., Amin M., Berney D., Comperat E., Gill A., Hartmann A., Menon S., Raspollini M., Rubin M., Srigley J., et al. The 2022 world health organization classification of tumors of the urinary system and male genital organs-part b: Prostate and urinary tract tumors. Eur. Urol. 2022;82:469–482. doi: 10.1016/j.eururo.2022.07.002. - DOI - PubMed

[6] Netto G.J., Amin M., Berney D., Comperat E., Gill A., Hartmann A., Menon S., Raspollini M., Rubin M., Srigley J., et al. The 2022 world health organization classification of tumors of the urinary system and male genital organs-part b: Prostate and urinary tract tumors. Eur. Urol. 2022;82:469–482. doi: 10.1016/j.eururo.2022.07.002. - DOI - PubMed

[7] Comperat E., McKenney J., Hartmann A., Hes O., Bertz S., Varinot J., Brimo F. Large nested variant of urothelial carcinoma: A clinicopathological study of 36 cases. Histopathology. 2017;71:703–710. doi: 10.1111/his.13280. - DOI - PubMed

[8] Comperat E., McKenney J., Hartmann A., Hes O., Bertz S., Varinot J., Brimo F. Large nested variant of urothelial carcinoma: A clinicopathological study of 36 cases. Histopathology. 2017;71:703–710. doi: 10.1111/his.13280. - DOI - PubMed

[9] Weyerer V., Eckstein M., Comperat E., Juette H., Gaisa N., Allory Y., Stohr R., Wullich B., Roupret M., Hartmann A., et al. Pure large nested variant of urothelial carcinoma (lnuc) is the prototype of an fgfr3 mutated aggressive urothelial carcinoma with luminal-papillary phenotype. Cancers. 2020;12:763. doi: 10.3390/cancers12030763. - DOI - PMC - PubMed

[10] Weyerer V., Eckstein M., Comperat E., Juette H., Gaisa N., Allory Y., Stohr R., Wullich B., Roupret M., Hartmann A., et al. Pure large nested variant of urothelial carcinoma (lnuc) is the prototype of an fgfr3 mutated aggressive urothelial carcinoma with luminal-papillary phenotype. Cancers. 2020;12:763. doi: 10.3390/cancers12030763. - DOI - PMC - PubMed

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Large, Nested Variant of Urothelial Carcinoma Is Enriched with Activating Mutations in Fibroblast Growth Factor Receptor-3 among Other Targetable Mutations

Affiliations

Large, Nested Variant of Urothelial Carcinoma Is Enriched with Activating Mutations in Fibroblast Growth Factor Receptor-3 among Other Targetable Mutations

Authors

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Abstract

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Abstract

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