PMID- 32047230 OWN - NLM STAT- MEDLINE DCOM- 20210708 LR - 20230210 IS - 1530-0285 (Electronic) IS - 0893-3952 (Linking) VI - 33 IP - 7 DP - 2020 Jul TI - Variant morphology and random chromosomal integration of BK polyomavirus in posttransplant urothelial carcinomas. PG - 1433-1442 LID - 10.1038/s41379-020-0489-0 [doi] AB - 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. FAU - Bertz, Simone AU - Bertz S AD - Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Ensser, Armin AU - Ensser A AD - Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Stoehr, Robert AU - Stoehr R AD - Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Eckstein, Markus AU - Eckstein M AD - Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Apel, Hendrik AU - Apel H AD - Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Mayr, Doris AU - Mayr D AD - Institute of Pathology, Ludwig Maximilians University Munich, 80337, Munich, Germany. FAU - Buettner-Herold, Maike AU - Buettner-Herold M AD - Department of Nephropathology, University Hospital Erlangen, Friedrich-Alexander Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Gaisa, Nadine Therese AU - Gaisa NT AD - Institute of Pathology, RWTH Aachen University, 52074, Aachen, Germany. FAU - Comperat, Eva AU - Comperat E AD - Department of Pathology, Pitie-Salpetriere Hospital, UPMC, 75013, Paris, France. FAU - Wullich, Bernd AU - Wullich B AD - Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Hartmann, Arndt AU - Hartmann A AD - Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. FAU - Knoll, Antje AU - Knoll A AUID- ORCID: 0000-0002-1294-6923 AD - Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander Universitat Erlangen-Nurnberg, 91054, Erlangen, Germany. antje.knoell@uk-erlangen.de. LA - eng PT - Journal Article DEP - 20200211 PL - United States TA - Mod Pathol JT - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc JID - 8806605 RN - 0 (Antigens, Viral, Tumor) SB - IM MH - Adult MH - Aged MH - Antigens, Viral, Tumor/analysis MH - BK Virus MH - Carcinoma, Transitional Cell/*immunology/*virology MH - Child MH - Female MH - Humans MH - *Immunocompromised Host MH - Male MH - Middle Aged MH - Polyomavirus Infections/*immunology MH - Transplant Recipients MH - Tumor Virus Infections/*immunology EDAT- 2020/02/13 06:00 MHDA- 2021/07/09 06:00 CRDT- 2020/02/13 06:00 PHST- 2019/10/25 00:00 [received] PHST- 2020/01/29 00:00 [accepted] PHST- 2020/01/26 00:00 [revised] PHST- 2020/02/13 06:00 [pubmed] PHST- 2021/07/09 06:00 [medline] PHST- 2020/02/13 06:00 [entrez] AID - S0893-3952(22)00826-2 [pii] AID - 10.1038/s41379-020-0489-0 [doi] PST - ppublish SO - Mod Pathol. 2020 Jul;33(7):1433-1442. doi: 10.1038/s41379-020-0489-0. Epub 2020 Feb 11.