Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis.
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.
Koul
Anjila
A
Department of Oncology, Lund University Hospital, Lund, Sweden. anjila.koul@onk.lu.se
Willén
Roger
R
Bendahl
Pär-Ola
PO
Nilbert
Mef
M
Borg
Ake
A
D000368:Aged; D003598:Cytoskeletal Proteins / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D006965:Hyperplasia; D007593:Joint Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D011003:Ploidies; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015534:Trans-Activators; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051176:beta Catenin; D018631:ras Proteins
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins