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Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma

Sjödahl, Gottfrid LU ; Eriksson, Pontus LU ; Patschan, Oliver LU ; Marzouka, Nour Al Dain LU ; Jakobsson, Lovisa LU ; Bernardo, Carina LU orcid ; Lövgren, Kristina LU ; Chebil, Gunilla ; Zwarthoff, Ellen and Liedberg, Fredrik LU , et al. (2020) In International Journal of Cancer 146(9). p.2636-2647
Abstract

Molecular changes occurring during invasion and clinical progression of cancer are difficult to study longitudinally in patient-derived material. A unique feature of urothelial bladder cancer (UBC) is that patients frequently develop multiple nonmuscle invasive tumors, some of which may eventually progress to invade the muscle of the bladder wall. Here, we use a cohort of 73 patients that experienced a total of 357 UBC diagnoses to study the stability or change in detected molecular alterations during cancer progression. The tumors were subtyped by gene expression profiling and analyzed for hotspot mutations in FGFR3, PIK3CA and TERT, the most frequent early driver mutations in this tumor type. TP53 alterations, frequent in advanced... (More)

Molecular changes occurring during invasion and clinical progression of cancer are difficult to study longitudinally in patient-derived material. A unique feature of urothelial bladder cancer (UBC) is that patients frequently develop multiple nonmuscle invasive tumors, some of which may eventually progress to invade the muscle of the bladder wall. Here, we use a cohort of 73 patients that experienced a total of 357 UBC diagnoses to study the stability or change in detected molecular alterations during cancer progression. The tumors were subtyped by gene expression profiling and analyzed for hotspot mutations in FGFR3, PIK3CA and TERT, the most frequent early driver mutations in this tumor type. TP53 alterations, frequent in advanced UBC, were inferred from p53 staining pattern, and potential genomic alterations were inferred by gene expression patterns at regions harboring frequent copy number alterations. We show that early driver mutations were largely preserved in UBC recurrences. Changes in FGFR3, PIK3CA or TERT mutation status were not linked to changes in molecular subtype and aggressive behavior. Instead, changes into a more aggressive molecular subtype seem to be associated with p53 alterations. We analyze changes in gene expression from primary tumors, to recurrences and progression tumors, and identify two modes of progression: Patients for whom progression is preceded by or coincides with a radical subtype shift, and patients who progress without any systematic molecular changes. For the latter group of patients, progression may be either stochastic or depending on factors already present at primary tumor initiation.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
bladder cancer, molecular subtypes, mutation, progression, urothelial carcinoma
in
International Journal of Cancer
volume
146
issue
9
pages
12 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:31609466
  • scopus:85075301229
ISSN
0020-7136
DOI
10.1002/ijc.32737
language
English
LU publication?
yes
id
c7eefa2b-3aed-4913-a239-d504a08e848e
date added to LUP
2019-12-09 10:44:41
date last changed
2024-04-02 20:11:43
@article{c7eefa2b-3aed-4913-a239-d504a08e848e,
  abstract     = {{<p>Molecular changes occurring during invasion and clinical progression of cancer are difficult to study longitudinally in patient-derived material. A unique feature of urothelial bladder cancer (UBC) is that patients frequently develop multiple nonmuscle invasive tumors, some of which may eventually progress to invade the muscle of the bladder wall. Here, we use a cohort of 73 patients that experienced a total of 357 UBC diagnoses to study the stability or change in detected molecular alterations during cancer progression. The tumors were subtyped by gene expression profiling and analyzed for hotspot mutations in FGFR3, PIK3CA and TERT, the most frequent early driver mutations in this tumor type. TP53 alterations, frequent in advanced UBC, were inferred from p53 staining pattern, and potential genomic alterations were inferred by gene expression patterns at regions harboring frequent copy number alterations. We show that early driver mutations were largely preserved in UBC recurrences. Changes in FGFR3, PIK3CA or TERT mutation status were not linked to changes in molecular subtype and aggressive behavior. Instead, changes into a more aggressive molecular subtype seem to be associated with p53 alterations. We analyze changes in gene expression from primary tumors, to recurrences and progression tumors, and identify two modes of progression: Patients for whom progression is preceded by or coincides with a radical subtype shift, and patients who progress without any systematic molecular changes. For the latter group of patients, progression may be either stochastic or depending on factors already present at primary tumor initiation.</p>}},
  author       = {{Sjödahl, Gottfrid and Eriksson, Pontus and Patschan, Oliver and Marzouka, Nour Al Dain and Jakobsson, Lovisa and Bernardo, Carina and Lövgren, Kristina and Chebil, Gunilla and Zwarthoff, Ellen and Liedberg, Fredrik and Höglund, Mattias}},
  issn         = {{0020-7136}},
  keywords     = {{bladder cancer; molecular subtypes; mutation; progression; urothelial carcinoma}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{9}},
  pages        = {{2636--2647}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{International Journal of Cancer}},
  title        = {{Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma}},
  url          = {{http://dx.doi.org/10.1002/ijc.32737}},
  doi          = {{10.1002/ijc.32737}},
  volume       = {{146}},
  year         = {{2020}},
}