Universität zu Köln

Garczyk, Stefan, Ortiz-Bruechle, Nadina, Schneider, Ursula, Lurje, Isabella, Guricova, Karolina, Gaisa, Nadine T., Lorsy, Eva, Lindemann-Docter, Katharina, Heidenreich, Axel and Knuechel, Ruth (2020). Next-Generation Sequencing Reveals Potential Predictive Biomarkers and Targets of Therapy for Urothelial Carcinoma in Situ of the Urinary Bladder. Am. J. Pathol., 190 (2). S. 323 - 333. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1525-2191

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Abstract

Bacillus Calmette-Guerin instillation after removal of the tumor is the first line of treatment for urothelial carcinoma in situ (CIS), the precursor lesion of most muscle-invasive bladder cancers. Bacillus Calmette-Guerin therapy fails in >50% of cases, and second-line radical cystectomy is associated with overtreatment and drastic lifestyle consequences. Given the need for alternative bladder-preserving therapies, we identified genomic alterations (GAs) in urothelial CIS having the potential to predict response to targeted therapies. Laser-capture microdissection was applied to isolate 30 samples (25 CIS and 5 muscle controls) from 26 fresh-frozen cystectomy specimens. Targeted next-generation sequencing of 31 genes was performed. The panel comprised genes frequently affected in muscle invasive bladder cancer of nonpapillary origin, focusing on potentially actionable GAs described to predict response to approved targeted therapies or drugs that are in registered clinical trials. Of CIS patients, 92% harbored at least one potentially actionable GA, which was identified in TP53/cell cycle pathway related genes (eg, TP53 and MDM2) in 72%, genes encoding chromatin-modifying proteins (eg, ARID1A and KDM6A) in 68%, DNA damage repair genes (eg, BRCA2 and ATM) in 60%, and phosphatidylinositol 3-kinase/mitogen-activated protein kinase pathway genes (eg, ERBB2 and FGFR1) in 36% of the cases. These data might help guide the selection of targeted therapies to be investigated in future clinical CIS trials, and they may provide a basis for future mechanistic studies of urothelial CIS pathogenesis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Garczyk, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Ortiz-Bruechle, Nadina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Ursula UNSPECIFIED UNSPECIFIED UNSPECIFIED Lurje, Isabella UNSPECIFIED UNSPECIFIED UNSPECIFIED Guricova, Karolina UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaisa, Nadine T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lorsy, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Lindemann-Docter, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Heidenreich, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Knuechel, Ruth UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-347708
DOI:	10.1016/j.ajpath.2019.10.004
Journal or Publication Title:	Am. J. Pathol.
Volume:	190
Number:	2
Page Range:	S. 323 - 333
Date:	2020
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1525-2191
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COMPREHENSIVE MOLECULAR CHARACTERIZATION; ADVANCED SOLID TUMORS; DNA-DAMAGE; SYNTHETIC LETHALITY; GENETIC ALTERATIONS; TERT PROMOTER; CANCER-CELLS; INHIBITOR; SENSITIVITY; MANAGEMENT Multiple languages Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34770