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Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

Koul, Anjila LU ; Willen, R; Bendahl, Pär-Ola LU ; Nilbert, Mef LU and Borg, Åke LU (2002) In Cancer 94(9). p.2369-2379
Abstract
BACKGROUND. Endometrial carcinomas seem to carry a different prognosis depending on the presence or absence of concomitant complex atypical hyperplasia (hyperplasia). The molecular genetic profile of these two pathogenetic types, based on the genes reportedly mutated in these cancers, remains to be defined. Although microsatellite inability is reported in approximately 25% of endometrial carcinomas, its relation with the 2 pathogenetic types is not investigated. METHODS. To elucidate their underlying genetic changes, we analyzed 53 sporadic endometrial tumors, including 19 with and 34 without hyperplasia, for microsatellite instability (MSI), DNA ploidy (by flow cytometry), and for mutations in different genes. RESULTS. Microsatellite... (More)
BACKGROUND. Endometrial carcinomas seem to carry a different prognosis depending on the presence or absence of concomitant complex atypical hyperplasia (hyperplasia). The molecular genetic profile of these two pathogenetic types, based on the genes reportedly mutated in these cancers, remains to be defined. Although microsatellite inability is reported in approximately 25% of endometrial carcinomas, its relation with the 2 pathogenetic types is not investigated. METHODS. To elucidate their underlying genetic changes, we analyzed 53 sporadic endometrial tumors, including 19 with and 34 without hyperplasia, for microsatellite instability (MSI), DNA ploidy (by flow cytometry), and for mutations in different genes. RESULTS. Microsatellite instability was present in 21%, DNA nondiploidy in 15%, and mutations in the PTEN, KRAS, CTNNB1/beta-catenin, TP53, and CDKN2A genes were detected in 32, 11, 13, 17, and 0% of the tumors, respectively. Microsatellite instability and mutations in these genes were present in tumors both with and without complex atypical hyperplasia. All cases with complex atypical hyperplasia were early stage (I-II) endometrioid tumors and associated with long progression free disease (P = 0.0004). Furthermore, most tumors with hyperplasia had low World Health Organization or International Federation of Gynecology and Obstetrics grade, had less myometrial invasion, and showed expression of estrogen receptors. All MSI tumors were diploid and had a significantly higher rate of PTEN mutations, but similar rates of KRAS, beta-catenin, and TP53 mutations compared with microsatellite stable tumors. TP53 mutations more often were found in nondiploid tumors but never in tumors with PTEN, KRAS, or beta-catenin mutations, and all PTEN mutations occurred in diploid tumors. CONCLUSIONS. Thus, PTEN, KRAS, beta-catenin, and TP53 mutations occurred in tumors both with and without hyperplasia, but PTEN and TP53 mutations were more common in tumors without hyperplasia. However, none of these genes seems to clearly distinguish tumors with and without hyperplasia, suggesting that other factors may be involved. Conversely, alterations in the PTEN and TP53 genes seem to define distinct subgroups of endometrial carcinoma, the former associated with diploidy and MSI, the latter with macroscopic chromosomal instability. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
microsatellite, endometrial carcinoma, complex atypical hyperplasia, instability, DNA ploidy
in
Cancer
volume
94
issue
9
pages
2369 - 2379
publisher
John Wiley & Sons
external identifiers
  • wos:000175310200008
  • pmid:12015762
  • scopus:0036569795
ISSN
1097-0142
DOI
10.1002/cncr.10498
language
English
LU publication?
yes
id
91a3d4c0-1409-48df-9444-10ed11da875e (old id 339658)
date added to LUP
2007-10-31 09:41:33
date last changed
2017-09-17 05:26:32
@article{91a3d4c0-1409-48df-9444-10ed11da875e,
  abstract     = {BACKGROUND. Endometrial carcinomas seem to carry a different prognosis depending on the presence or absence of concomitant complex atypical hyperplasia (hyperplasia). The molecular genetic profile of these two pathogenetic types, based on the genes reportedly mutated in these cancers, remains to be defined. Although microsatellite inability is reported in approximately 25% of endometrial carcinomas, its relation with the 2 pathogenetic types is not investigated. METHODS. To elucidate their underlying genetic changes, we analyzed 53 sporadic endometrial tumors, including 19 with and 34 without hyperplasia, for microsatellite instability (MSI), DNA ploidy (by flow cytometry), and for mutations in different genes. RESULTS. Microsatellite instability was present in 21%, DNA nondiploidy in 15%, and mutations in the PTEN, KRAS, CTNNB1/beta-catenin, TP53, and CDKN2A genes were detected in 32, 11, 13, 17, and 0% of the tumors, respectively. Microsatellite instability and mutations in these genes were present in tumors both with and without complex atypical hyperplasia. All cases with complex atypical hyperplasia were early stage (I-II) endometrioid tumors and associated with long progression free disease (P = 0.0004). Furthermore, most tumors with hyperplasia had low World Health Organization or International Federation of Gynecology and Obstetrics grade, had less myometrial invasion, and showed expression of estrogen receptors. All MSI tumors were diploid and had a significantly higher rate of PTEN mutations, but similar rates of KRAS, beta-catenin, and TP53 mutations compared with microsatellite stable tumors. TP53 mutations more often were found in nondiploid tumors but never in tumors with PTEN, KRAS, or beta-catenin mutations, and all PTEN mutations occurred in diploid tumors. CONCLUSIONS. Thus, PTEN, KRAS, beta-catenin, and TP53 mutations occurred in tumors both with and without hyperplasia, but PTEN and TP53 mutations were more common in tumors without hyperplasia. However, none of these genes seems to clearly distinguish tumors with and without hyperplasia, suggesting that other factors may be involved. Conversely, alterations in the PTEN and TP53 genes seem to define distinct subgroups of endometrial carcinoma, the former associated with diploidy and MSI, the latter with macroscopic chromosomal instability.},
  author       = {Koul, Anjila and Willen, R and Bendahl, Pär-Ola and Nilbert, Mef and Borg, Åke},
  issn         = {1097-0142},
  keyword      = {microsatellite,endometrial carcinoma,complex atypical hyperplasia,instability,DNA ploidy},
  language     = {eng},
  number       = {9},
  pages        = {2369--2379},
  publisher    = {John Wiley & Sons},
  series       = {Cancer},
  title        = {Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis},
  url          = {http://dx.doi.org/10.1002/cncr.10498},
  volume       = {94},
  year         = {2002},
}