Konopka Bozena, Janiec-Jankowska Aneta, Czapczak Dorota, Paszko Zygmunt, Bidziński Mariusz, Olszewski Włodzimierz, Goluda Cyprian
Endocrinology Department, The Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, 5 W.K. Roentgen Street, 02-781 Warsaw, Poland.
J Cancer Res Clin Oncol. 2007 Jun;133(6):361-71. doi: 10.1007/s00432-006-0179-4. Epub 2007 Jan 12.
The present study aims to assess the incidence of microsatellite instability (MSI) and mutations in the PTEN and beta-catenin (CTNNB1) genes in endometrial carcinomas and to analyze the detected defects in these factors in relation to each other and to the clinico-pathological features of tumors.
In a series of 56 endometrioid endometrial carcinomas, the status of MSI was determined using nine polymorphic markers, and mutations in all exons of the PTEN gene and in exon 3 of the CTNNB1 gene were evaluated by SSCP and sequencing methods.
Microsatellite instability was found in 18 carcinomas (32.1%, MSI+); the remaining 38 tumors were microsatellite stable (MSI-). In 15 cases (26.8%), a loss of heterozygosity (LOH) at the studied microsatellite markers also occurred. In 29 carcinomas (51.8%), mutations were found in the PTEN gene and in nine tumors (16.1%) in the CTNNB1 gene. PTEN mutations occurred significantly more frequently in MSI+ than in MSI- tumors (77.8 vs. 39.5%, p = 0.007), but, except for one, none of them was attributable to MSI. In contrast, incidence of CTNNB1 mutations in MSI+ and MSI- tumors no significantly differed between themselves (16.7 vs. 15.8%, p = 0.760). Interestingly, mutations in the CTNNB1 gene most frequently coexisted with mutations in the PTEN gene (7/9, 77.8%). However, this finding requires future verification on a larger group of cases. The incidence of MSI and PTEN, but not CTNNB1 mutations, was significantly more common in poorly, than in well-to-moderately, differentiated tumors (G3 vs. G1 + G2; p = 0.042, 0.039 and 0.958, respectively).
We conclude that most frequently occurring mutations in the PTEN gene may be a key event for the tumorigenesis of endometrioid endometrial carcinomas, while coexistence or absence of microsatellite instability or mutations in the CTNNB1 gene may reflect the heterogeneity of molecular mechanisms contributing to the development of these tumors.
本研究旨在评估子宫内膜癌中微卫星不稳定性（MSI）的发生率以及PTEN和β-连环蛋白（CTNNB1）基因的突变情况，并分析这些因素中检测到的缺陷之间的相互关系以及与肿瘤临床病理特征的关系。
在一系列56例子宫内膜样腺癌中，使用9个多态性标记物确定MSI状态，并通过SSCP和测序方法评估PTEN基因所有外显子以及CTNNB1基因第3外显子的突变情况。
在18例癌（32.1%，MSI+）中发现微卫星不稳定性；其余38例肿瘤微卫星稳定（MSI-）。在15例（26.8%）中，在所研究的微卫星标记物处也发生了杂合性缺失（LOH）。在29例癌（51.8%）中发现PTEN基因突变，在9例肿瘤（16.1%）中发现CTNNB1基因突变。PTEN突变在MSI+肿瘤中比在MSI-肿瘤中显著更频繁发生（77.8%对39.5%，p = 0.007），但除1例之外，它们均不归因于MSI。相反，MSI+和MSI-肿瘤中CTNNB1突变的发生率彼此之间无显著差异（16.7%对15.8%，p = 0.760）。有趣的是，CTNNB1基因突变最常与PTEN基因突变共存（7/9，77.8%）。然而，这一发现需要在更大一组病例中进行进一步验证。MSI以及PTEN突变的发生率在低分化肿瘤中比在高分化至中分化肿瘤中显著更常见，但CTNNB1突变并非如此（G3对G1 + G2；p分别为0.042、0.039和0.958）。
我们得出结论，PTEN基因中最常发生的突变可能是子宫内膜样腺癌发生的关键事件，而微卫星不稳定性或CTNNB1基因突变的共存或缺失可能反映了导致这些肿瘤发生的分子机制的异质性。
