Variant morphology and random chromosomal integration of BK polyomavirus in posttransplant urothelial carcinomas

Bertz S, Enßer A, Stöhr R, Eckstein M, Apel H, Mayr D, Büttner-Herold M, Gaisa NT, Comperat E, Wullich B, Hartmann A, Knöll A (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Modern Pathology Nature Publishing Group: Open Access Hybrid Model Option B

DOI: 10.1038/s41379-020-0489-0

Abstract

BK polyomavirus (BKPyV) causes major complications in solid organ transplant recipients but little is known about its role in the development of urothelial carcinoma (UC) during immunosuppression. Immunohistochemistry (IHC) screening for polyomavirus large T antigen (LTag) was performed in 94 micropapillary UC (MPUC), 480 unselected UC, 199 muscle invasive UC (including 83 UC with variant differentiation), 76 cases of plasmocytoid, nested and large nested UC and 15 posttransplant UC. LTag expressing UC were reevaluated regarding their histomorphological features and characterized by IHC for p53 and HER2, chromogenic in situ hybridization for HER2 and SNaPshot analysis of the TERT promoter and HRAS. Real-time PCR and next generation sequencing (NGS) were performed to search for BKPyV-DNA and for variants in the tumor and viral genomes. We detected five LTag expressing UC which were diagnosed between 2 and 18 years after kidney (n = 4) or heart (n = 1) transplantation. 89 MPUC without history of organ transplantation and overall 755 UC (including cases with variant histology) were LTag negative. Of the five LTag expressing UC, three were MPUC, one showed extensive divergent differentiation with Mullerian type clear cell carcinoma, and one displayed focal villoglandular differentiation. All five tumors had aberrant nuclear p53 expression, 2/5 were HER2-amplified, and 3/5 had TERT promoter mutations. Within the 50 most common cancer related genes altered in UC we detected very few alterations and no TP53 mutations. BKPyV-DNA was present in 5/5 UC, chromosomal integration of the BKPyV genome was detectable in 4/5 UC. Two UC with BKPyV integration showed small deletions in the BKPyV noncoding control region (NCCR). The only UC without detectable BKPyV integration had a high viral load of human herpesvirus 6 (HHV-6). Our results suggest that LTag expression of integrated BKPyV genomes and resulting p53 inactivation lead to aggressive high-grade UC with unusual, often micropapillary morphology.

Authors with CRIS profile

Simone Bertz Institute of Pathology Armin Enßer Medizinische Fakultät Robert Stöhr Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Markus Eckstein Institute of Pathology Hendrik Apel Urologische Klinik Maike Büttner-Herold Medizinische Fakultät Bernd Wullich Lehrstuhl für Urologie Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Antje Knöll Institute of Clinical and Molecular Virology

Involved external institutions

Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen DE Germany (DE) University of Pittsburgh Medical Center (UPMC) US United States (USA) (US) Ludwig-Maximilians-Universität (LMU) DE Germany (DE)

How to cite

APA:

Bertz, S., Enßer, A., Stöhr, R., Eckstein, M., Apel, H., Mayr, D.,... Knöll, A. (2020). Variant morphology and random chromosomal integration of BK polyomavirus in posttransplant urothelial carcinomas. Modern Pathology. https://doi.org/10.1038/s41379-020-0489-0

MLA:

Bertz, Simone, et al. "Variant morphology and random chromosomal integration of BK polyomavirus in posttransplant urothelial carcinomas." Modern Pathology (2020).

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