Microsatellite instability in uterine sarcomas

Amant, Frédéric; Dorfling, Cecilia M.; Dreyer, L; Vergote, Ignace; Lindeque, Bennie; Rensburg, Elizabeth J. van

doi:10.1046/j.1525-1438.2001.01013.x

Cited by 31 publications

(22 citation statements)

References 26 publications

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“…Although MSI has been reported to be infrequent in uterine carcinosarcomas (B5%), 12,13 recent studies from our laboratory have suggested that MSI may be more common in uterine carcinosarcomas than previously described and that defective DNA mismatch repair may be a feature unique to the epithelial component of these tumors. [12][13][14] We therefore sought to determine the DNA mismatch repair and TP53 status in each component of uterine carcinosarcomas in an attempt to better understand the histiogenesis of these malignancies.…”

mentioning

confidence: 62%

DNA mismatch repair and TP53 defects are early events in uterine carcinosarcoma tumorigenesis

et al. 2006

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Growing molecular evidence shows that uterine carcinosarcomas are clonal tumors. The carcinoma component has a dominant effect in the aggressive clinical behavior of these tumors. Defective DNA mismatch repair affects up to 30% of endometrial adenocarcinomas. The frequency and importance of defective DNA mismatch repair in the histiogenesis of uterine carcinosarcomas remains controversial. We studied the pattern and frequency of defective DNA mismatch repair and TP53 alterations in the epithelial and mesenchymal components of 28 uterine carcinosarcomas. We found evidence of defective DNA mismatch repair in six cases (21%) with a concordance rate of 83% for carcinoma-sarcoma pairs (j ¼ 0.887, Po0.001). Lack of immunostaining for the MLH1 protein was demonstrated in both components in two of these tumors. TP53 defects were evaluated by 17p deletion analysis and p53 immunostaining. Nineteen carcinoma (68%) and 18 sarcoma (64%) components had evidence of either TP53 allelic loss or p53 overexpression. These defects proved clonal in 76% of cases (j ¼ 0.602, P ¼ 0.003). Our results indicate that defective DNA mismatch repair and TP53 defects are common early events in carcinosarcoma tumorigenesis. The high rate of concordance for these molecular defects between the carcinoma and sarcoma components adds to existing molecular evidence that carcinosarcomas are clonal malignancies. Keywords: carcinosarcoma; malignant mixed mü llerian tumor; microsatellite instability; DNA mismatch repair; TP53; clonality Carcinosarcomas of the uterus account for 1-2% of all malignancies of the uterine corpus. The pathologic hallmark of these tumors is the presence of malignant epithelial and mesenchymal components. These mixed malignancies can affect any of the mü llerian derivatives of the female reproductive tract. Despite their relatively low incidence, these aggressive tumors represent a significant clinical problem. 1The overall survival at 5 years for all patients with cancer of the uterine corpus is 84% and only 31% for patients with a uterine carcinosarcoma. 2,3 There is clinical and molecular evidence suggesting that uterine carcinosarcomas are clonal malignancies. [4][5][6][7][8][9][10]

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confidence: 62%

DNA mismatch repair and TP53 defects are early events in uterine carcinosarcoma tumorigenesis

et al. 2006

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“…2,32,33 Microsatellite instability is caused by an inability of the MMR system to cut out and replace the mismatching DNA strains due to methylation or mutation of its proteins (MLH1, MSH2 and MSH6). 34 Two previous studies showed that microsatellite instability was present in 5% 35 and 23.3% 21 of uterine carcinosarcomas. The latter study observed that microsatellite instability is mainly a feature of the epithelial component.…”

Section: Discussionmentioning

confidence: 99%

Molecular markers and clinical behavior of uterine carcinosarcomas: focus on the epithelial tumor component

et al. 2011

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Carcinosarcomas (malignant mixed Mü llerian tumors) of the uterus are rare and aggressive malignancies consisting of an epithelial (carcinoma) and a mesenchymal (sarcoma) tumor component and are considered as metaplastic endometrial carcinomas. This study evaluated molecular characteristics and clinical behavior of uterine carcinosarcomas to improve treatment regimens in the future. Immunohistochemical expression of estrogen receptor-a and -b, progesterone receptor-A and -B, MLH1, MSH2, MSH6, PTEN (phosphatase and tensin homolog deleted on chromosome 10), p53, b-catenin and cyclin D1 was determined in 40 uterine carcinosarcomas. Immunostaining was compared between epithelial and mesenchymal tumor components. To determine the prognostic role of the epithelial component, clinicopathological data and survival were compared between patients with endometrioid and non-endometrioid epithelial tumor components. To determine prognosis of carcinosarcomas compared with high-risk endometrial carcinomas, clinicopathological characteristics and survival were compared between these patients. Hormone receptor expression occurred infrequently: estrogen receptor-a (8%) and -b (32%), progesterone receptor-A (0%) and -B (23%), next to b-catenin (4%) and cyclin D1 (7%). PTEN, MLH1, MSH2 and MSH6 mutations occurred in 39%, 33%, 22% and 21%, respectively (based on absent immunostaining). Overexpression of p53 was observed in 38%. Expression patterns of p53, MSH2 and MSH6 corresponded between epithelial and mesenchymal tumor components. In our cohort, the epithelial component caused the majority of metastases (72%) and vascular invasion (70%). Survival tended to be worse for patients with a non-endometrioid epithelial component compared with an endometrioid epithelial component (5-year survival: 26% and 55%, respectively). Survival was worse for patients with uterine carcinosarcomas compared with high-risk endometrial carcinomas (grade 3 endometrioid and non-endometrioid); 5-year survival rates: 42%, 77% and 57%, respectively. Our results support the monoclonal origin of uterine carcinosarcomas. The epithelial component determines prognosis by causing the majority of metastases and vascular invasion. To improve prognosis, treatment should focus on the epithelial tumor component of uterine carcinosarcomas. Modern Pathology (2011Pathology ( ) 24, 1368Pathology ( -1379 doi:10.1038/modpathol.2011; published online 13 May 2011Keywords: carcinogenesis; clinical behavior; epithelial component; immunohistochemistry; uterine carcinosarcomas Uterine carcinosarcomas (malignant mixed Mü llerian tumors) are rare malignancies of the female genital tract, accounting for 1-5% of uterine malignancies. 1,2 Microscopically, carcinosarcomas consist of two histological malignant components: an epithelial (carcinoma) and a mesenchymal (sarcoma) component. The epithelial component is usually a

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“…The same tumors were investigated also for LOH but the results were then less clear-cut. Amant et al (2001) found no LOH in the five tumors they examined. Moinfar et al (2004) studied a total of 27 tumors (20 ESS, four ESN, and three UES) as well as samples of non-tumorous surrounding tissue.…”

Section: Microsatellite Instability (Msi) and Loss Of Heterozygosity mentioning

confidence: 85%

Pathogenetic mechanisms in endometrial stromal sarcoma

Micci¹,

Heim²

2007

Cytogenet Genome Res

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Microsatellite instability in uterine sarcomas

Cited by 31 publications

References 26 publications

DNA mismatch repair and TP53 defects are early events in uterine carcinosarcoma tumorigenesis

DNA mismatch repair and TP53 defects are early events in uterine carcinosarcoma tumorigenesis

Molecular markers and clinical behavior of uterine carcinosarcomas: focus on the epithelial tumor component

Pathogenetic mechanisms in endometrial stromal sarcoma

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