Advanced

A Systematic Study of Gene Mutations in Urothelial Carcinoma; Inactivating Mutations in TSC2 and PIK3R1.

Sjödahl, Gottfrid LU ; Lauss, Martin LU ; Gudjonsson, Sigurdur LU ; Liedberg, Fredrik LU ; Halldén, Christer LU ; Chebil, Gunilla; Månsson, Wiking LU ; Höglund, Mattias LU and Lindgren, David LU (2011) In PLoS ONE 6(4).
Abstract
Abstract

BACKGROUND:

Urothelial carcinoma (UC) is characterized by frequent gene mutations of which activating mutations in FGFR3 are the most frequent. Several downstream targets of FGFR3 are also mutated in UC, e.g., PIK3CA, AKT1, and RAS. Most mutation studies of UCs have been focused on single or a few genes at the time or been performed on small sample series. This has limited the possibility to investigate co-occurrence of mutations.



METHODOLOGY/PRINCIPAL FINDINGS:

We performed mutation analyses of 16 genes, FGFR3, PIK3CA, PIK3R1 PTEN, AKT1, KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, TSC1, TSC2, APC, CTNNB1, and TP53, in 145 cases of UC. We show that FGFR3 and PIK3CA mutations are positively... (More)
Abstract

BACKGROUND:

Urothelial carcinoma (UC) is characterized by frequent gene mutations of which activating mutations in FGFR3 are the most frequent. Several downstream targets of FGFR3 are also mutated in UC, e.g., PIK3CA, AKT1, and RAS. Most mutation studies of UCs have been focused on single or a few genes at the time or been performed on small sample series. This has limited the possibility to investigate co-occurrence of mutations.



METHODOLOGY/PRINCIPAL FINDINGS:

We performed mutation analyses of 16 genes, FGFR3, PIK3CA, PIK3R1 PTEN, AKT1, KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, TSC1, TSC2, APC, CTNNB1, and TP53, in 145 cases of UC. We show that FGFR3 and PIK3CA mutations are positively associated. In addition, we identified PIK3R1 as a target for mutations. We demonstrate a negative association at borderline significance between FGFR3 and RAS mutations, and show that these mutations are not strictly mutually exclusive. We show that mutations in BRAF, ARAF, RAF1 rarely occurs in UC. Our data emphasize the possible importance of APC signaling as 6% of the investigated tumors either showed inactivating APC or activating CTNNB1 mutations. TSC1, as well as TSC2, that constitute the mTOR regulatory tuberous sclerosis complex were found to be mutated at a combined frequency of 15%.



CONCLUSIONS/SIGNIFICANCE:

Our data demonstrate a significant association between FGFR3 and PIK3CA mutations in UC. Moreover, the identification of mutations in PIK3R1 further emphasizes the importance of the PI3-kinase pathway in UC. The presence of TSC2 mutations, in addition to TSC1 mutations, underlines the involvement of mTOR signaling in UC. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
6
issue
4
publisher
Public Library of Science
external identifiers
  • wos:000289505600011
  • scopus:79955012093
ISSN
1932-6203
DOI
10.1371/journal.pone.0018583
language
English
LU publication?
yes
id
15f56c2d-a781-4e34-aacd-518eca185462 (old id 1973298)
alternative location
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077383/pdf/pone.0018583.pdf
http://www.ncbi.nlm.nih.gov/pubmed/21533174?dopt=Abstract
date added to LUP
2011-06-07 10:15:14
date last changed
2017-10-29 03:56:19
@article{15f56c2d-a781-4e34-aacd-518eca185462,
  abstract     = {Abstract<br/><br>
BACKGROUND:<br/><br>
Urothelial carcinoma (UC) is characterized by frequent gene mutations of which activating mutations in FGFR3 are the most frequent. Several downstream targets of FGFR3 are also mutated in UC, e.g., PIK3CA, AKT1, and RAS. Most mutation studies of UCs have been focused on single or a few genes at the time or been performed on small sample series. This has limited the possibility to investigate co-occurrence of mutations.<br/><br>
<br/><br>
METHODOLOGY/PRINCIPAL FINDINGS:<br/><br>
We performed mutation analyses of 16 genes, FGFR3, PIK3CA, PIK3R1 PTEN, AKT1, KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, TSC1, TSC2, APC, CTNNB1, and TP53, in 145 cases of UC. We show that FGFR3 and PIK3CA mutations are positively associated. In addition, we identified PIK3R1 as a target for mutations. We demonstrate a negative association at borderline significance between FGFR3 and RAS mutations, and show that these mutations are not strictly mutually exclusive. We show that mutations in BRAF, ARAF, RAF1 rarely occurs in UC. Our data emphasize the possible importance of APC signaling as 6% of the investigated tumors either showed inactivating APC or activating CTNNB1 mutations. TSC1, as well as TSC2, that constitute the mTOR regulatory tuberous sclerosis complex were found to be mutated at a combined frequency of 15%.<br/><br>
<br/><br>
CONCLUSIONS/SIGNIFICANCE:<br/><br>
Our data demonstrate a significant association between FGFR3 and PIK3CA mutations in UC. Moreover, the identification of mutations in PIK3R1 further emphasizes the importance of the PI3-kinase pathway in UC. The presence of TSC2 mutations, in addition to TSC1 mutations, underlines the involvement of mTOR signaling in UC.},
  articleno    = {e18583},
  author       = {Sjödahl, Gottfrid and Lauss, Martin and Gudjonsson, Sigurdur and Liedberg, Fredrik and Halldén, Christer and Chebil, Gunilla and Månsson, Wiking and Höglund, Mattias and Lindgren, David},
  issn         = {1932-6203},
  language     = {eng},
  number       = {4},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {A Systematic Study of Gene Mutations in Urothelial Carcinoma; Inactivating Mutations in TSC2 and PIK3R1.},
  url          = {http://dx.doi.org/10.1371/journal.pone.0018583},
  volume       = {6},
  year         = {2011},
}