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Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome.

Lindgren, David LU ; Frigyesi, Attila LU ; Gudjonsson, Sigurdur LU ; Sjödahl, Gottfrid LU ; Halldén, Christer LU ; Chebil, Gunilla; Veerla, Srinivas LU ; Ryden, Tobias; Månsson, Wiking LU and Liedberg, Fredrik LU , et al. (2010) In Cancer Research 70(9). p.3463-3472
Abstract
In the present investigation, we sought to refine the classification of urothelial carcinoma by combining information on gene expression, genomic, and gene mutation levels. For these purposes, we performed gene expression analysis of 144 carcinomas, and whole genome array-CGH analysis and mutation analyses of FGFR3, PIK3CA, KRAS, HRAS, NRAS, TP53, CDKN2A, and TSC1 in 103 of these cases. Hierarchical cluster analysis identified two intrinsic molecular subtypes, MS1 and MS2, which were validated and defined by the same set of genes in three independent bladder cancer data sets. The two subtypes differed with respect to gene expression and mutation profiles, as well as with the level of genomic instability. The data show that genomic... (More)
In the present investigation, we sought to refine the classification of urothelial carcinoma by combining information on gene expression, genomic, and gene mutation levels. For these purposes, we performed gene expression analysis of 144 carcinomas, and whole genome array-CGH analysis and mutation analyses of FGFR3, PIK3CA, KRAS, HRAS, NRAS, TP53, CDKN2A, and TSC1 in 103 of these cases. Hierarchical cluster analysis identified two intrinsic molecular subtypes, MS1 and MS2, which were validated and defined by the same set of genes in three independent bladder cancer data sets. The two subtypes differed with respect to gene expression and mutation profiles, as well as with the level of genomic instability. The data show that genomic instability was the most distinguishing genomic feature of MS2 tumors, and that this trait was not dependent on TP53/MDM2 alterations. By combining molecular and pathologic data, it was possible to distinguish two molecular subtypes of T(a) and T(1) tumors, respectively. In addition, we define gene signatures validated in two independent data sets that classify urothelial carcinoma into low-grade (G(1)/G(2)) and high-grade (G(3)) tumors as well as non-muscle and muscle-invasive tumors with high precisions and sensitivities, suggesting molecular grading as a relevant complement to standard pathologic grading. We also present a gene expression signature with independent prognostic effect on metastasis and disease-specific survival. We conclude that the combination of molecular and histopathologic classification systems might provide a strong improvement for bladder cancer classification and produce new insights into the development of this tumor type. (Less)
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Contribution to journal
publication status
published
subject
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Cancer Research
volume
70
issue
9
pages
3463 - 3472
publisher
American Association for Cancer Research
external identifiers
  • WOS:000278486200006
  • PMID:20406976
  • Scopus:77951756330
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-09-4213
language
English
LU publication?
yes
id
016a0d41-3083-447a-b36f-9f08e603a525 (old id 1594987)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20406976?dopt=Abstract
date added to LUP
2010-05-04 21:22:28
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2016-12-04 04:40:08
@misc{016a0d41-3083-447a-b36f-9f08e603a525,
  abstract     = {In the present investigation, we sought to refine the classification of urothelial carcinoma by combining information on gene expression, genomic, and gene mutation levels. For these purposes, we performed gene expression analysis of 144 carcinomas, and whole genome array-CGH analysis and mutation analyses of FGFR3, PIK3CA, KRAS, HRAS, NRAS, TP53, CDKN2A, and TSC1 in 103 of these cases. Hierarchical cluster analysis identified two intrinsic molecular subtypes, MS1 and MS2, which were validated and defined by the same set of genes in three independent bladder cancer data sets. The two subtypes differed with respect to gene expression and mutation profiles, as well as with the level of genomic instability. The data show that genomic instability was the most distinguishing genomic feature of MS2 tumors, and that this trait was not dependent on TP53/MDM2 alterations. By combining molecular and pathologic data, it was possible to distinguish two molecular subtypes of T(a) and T(1) tumors, respectively. In addition, we define gene signatures validated in two independent data sets that classify urothelial carcinoma into low-grade (G(1)/G(2)) and high-grade (G(3)) tumors as well as non-muscle and muscle-invasive tumors with high precisions and sensitivities, suggesting molecular grading as a relevant complement to standard pathologic grading. We also present a gene expression signature with independent prognostic effect on metastasis and disease-specific survival. We conclude that the combination of molecular and histopathologic classification systems might provide a strong improvement for bladder cancer classification and produce new insights into the development of this tumor type.},
  author       = {Lindgren, David and Frigyesi, Attila and Gudjonsson, Sigurdur and Sjödahl, Gottfrid and Halldén, Christer and Chebil, Gunilla and Veerla, Srinivas and Ryden, Tobias and Månsson, Wiking and Liedberg, Fredrik and Höglund, Mattias},
  issn         = {1538-7445},
  language     = {eng},
  number       = {9},
  pages        = {3463--3472},
  publisher    = {ARRAY(0x9751828)},
  series       = {Cancer Research},
  title        = {Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-09-4213},
  volume       = {70},
  year         = {2010},
}