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Alternative strategies beyond current chemotherapy and radiation therapy regimens are needed in the treatment of advanced stage and recurrent endometrial cancers. There is considerable promise for biologic agents targeting the extracellular signal-regulated kinase (ERK) pathway for treatment of these cancers. Many downstream substrates of the ERK signaling pathway, such as glycogen synthase kinase 3ß (GSK3ß), and their roles in endometrial carcinogenesis have not yet been investigated. In this study, we tested the importance of GSK3ß inhibition in endometrial cancer cell lines and in vivo models. Inhibition of GSK3ß by either lithium chloride (LiCl) or specific GSK3ß inhibitor VIII showed cytostatic and cytotoxic effects on multiple endometrial cancer cell lines, with little effect on the immortalized normal endometrial cell line. Flow cytometry and immunofluorescence revealed a G2/M cell cycle arrest in both type I (AN3CA, KLE, and RL952) and type II (ARK1) endometrial cancer cell lines. In addition, LiCl pre-treatment sensitized AN3CA cells to the chemotherapy agent paclitaxel. Administration of LiCl to AN3CA tumor-bearing mice resulted in partial or complete regression of some tumors. Thus, GSK3ß activity is associated with endometrial cancer tumorigenesis and its pharmacologic inhibition reduces cell proliferation and tumor growth. [ABSTRACT FROM AUTHOR]

BACKGROUND: Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain. METHODS: Using targeted capture and massively parallel genomic sequencing, 151 subjects with USC were assessed for germline mutations in 30 tumor suppressor genes, including BRCA1 (breast cancer 1, early onset), BRCA2, the DNA mismatch repair genes ( MLH1 [mutL homolog 1], MSH2 [mutS homolog 2], MSH6, PMS2 [postmeiotic segregation increased 2]), TP53 (tumor protein p53), and 10 other genes in the Fanconi anemia-BRCA pathway. Ten cases with < 10% serous histology were also assessed. RESULTS: Seven subjects (4.6%) carried germline loss-of-function mutations: 3 subjects (2.0%) with mutations in BRCA1, 2 subjects (1.3%) with mutations in TP53, and 2 subjects (1.3%) with mutations in CHEK2 (checkpoint kinase 2). One subject with < 10% serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li-Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9%, compared to 0.9% in 119 women with no such history. CONCLUSIONS: Approximately 5% of women with USC have germline mutations in 3 different tumor suppressor genes : BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2% is higher than expected in a nonfounder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The clinicopathologic significance of lower uterine segment involvement (LUSI) in endometrial cancer patients remains unclear. Although LUSI has been reported to be a prognostic indicator, literature is limited. Methods: We studied 481 surgically staged endometrioid endometrial cancers with disease confined to the uterus (FIGO 1988 stage I or II). Primary outcomes were overall survival (OS) and disease-free survival (DFS). The relationships between LUSI and OS and DFS were assessed using the Kaplan-Meier method and Cox proportional hazard models. The t test or Fisher exact test was used for evaluating relationships between variables of interest. Results: LUSI was present in 223 cases (46.4%), and was associated with both decreased disease free survival ( P = 0.02) and overall survival ( P = 0.01) in univariate analysis. Multivariate analysis confirmed the association between LUSI and increased risk for recurrence [hazard ratio (HR) 2.27; 95% confidence interval (95% CI) 1.09-4.7; P = 0.03] and increased mortality (HR 1.76; 95% CI 1.12-2.78; P = 0.01). Conclusions: LUSI in patients with early-stage endometrioid endometrial cancer is associated with decreased survival. [ABSTRACT FROM AUTHOR]

The article discusses a study that applies whole-genome sequencing to a patient who had no significant family history of cancer but who had a suspected higher cancer susceptibility due to multiple primary tumors, with the aim of identifying rare or novel germline variants in cancer susceptibility genes. Skin and bone marrow DNA were acquired from the cancer patient. The samples were analyzed with whole-genome sequencing using paired-end reads, single-nucleotide polymorphism (SNP) genotyping, spectral karyotyping and RNA expression profiling.

The article focuses on a study about DICER1 expression and outcomes related to endometroid endometrial adenocarcinoma. The processes undertaken for the study are discussed which include loss of heterozygosity, methylation and statistical analyses. Results show that DICER1 expression levels tend to differ in primary endometroid endometrial tumors while lower transcripts are said to lead to the worse clinical outcomes. It suggests the future use of DICER1 expression assessment in risk assessment.

Simple Summary: Tumours of the colon and endometrium (lining of the womb) often have defects in genes that repair our DNA. Identifying these tumours is important for patient treatment and identifying Lynch syndrome (LS), an inherited cancer predisposition. However, the two methods most commonly used to identify these defects often give inconsistent results for endometrial tumours. Here, we investigate these inconsistencies by re-analysing 361 tumour samples from clinical trials with a third assay and establish that they are largely due to false positives in one assay (immunohistochemistry) and false negatives in the other (Promega MSI assay). In addition, the DNA repair defects seem to have a reduced impact within endometrial tumours. However, we find that tumours with defects in a gene called MSH6, especially when associated with LS, are only detected efficiently with immunohistochemistry. This supports current guidelines specifically recommending the use of this method for endometrial tumours. Background/Objectives: Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors. Colorectal cancers (CRCs) and endometrial cancers (ECs) are routinely screened to identify LS, primarily using immunohistochemistry (IHC) or microsatellite instability (MSI) testing, but concordance between these methods is variable in ECs. Here, we investigate this variability in 361 ECs from the Ohio OCCPI/OPTEC (n = 196) and Manchester PETALS (n = 165) trials, where concordance between assays differed significantly. Methods: Samples were re-tested using the amplicon-sequencing-based Newcastle MSI assay (NCL_MSI), and analysed with respect to existing IHC, MSI and MLH1 promoter hypermethylation data. Results: NCL_MSI showed consistency with the Ohio results (94% and 97% concordance with IHC and original MSI assays, respectively) and increased concordance within the Manchester cohort from 78% to 86% (MSI) and 84% (IHC). Among discordant Manchester samples, NCL_MSI was significantly associated with MLH1 promoter methylation status (p = 0.0028) and had the highest concordance with methylation, (62/69 samples, 90%), indicating utility as a screening tool in this tumour type. However, tumours with germline MSH6 defects were only detected efficiently with IHC; seven out of eight LS tumours classified as MSS by either MSI assay had isolated MSH6 loss, compared to four out of twelve classified as MSI-H by both (p = 0.028). Furthermore, reduced MSI signal was observed in tumours with isolated MSH6 loss (p = 0.009 Ohio, p = 6.2 × 10−5 Manchester) and in both ECs and CRCs with germline defects, although this only reached significance in CRCs (p = 0.002). Conclusions: These results provide further evidence that ECs with MSH6 loss in particular and LS tumours in general have an attenuated MSI signal, providing support for current guidelines specifically recommending IHC for LS detection and immune checkpoint therapy assessment in EC. [ABSTRACT FROM AUTHOR]

Defective DNA mismatch repair in human tumors leads to genome-wide instability of microsatellite repeats and a molecular phenotype referred to as microsatellite instability (MSI). MSI has been reported in a variety of cancers and is a consistent feature of tumors from patients with hereditary non-polyposis colorectal cancer. Approximately 20% of cancers of the uterine endometrium, the fifth most common cancer of women world-wide, exhibit MSI. Although the frequency of MSI is higher in endometrial cancers than in any other common malignancy, the genetic basis of MSI in these tumors has remained elusive. We investigated the role that methylation of the MLH1 DNA mismatch repair gene plays in the genesis of MSI in a large series of sporadic endometrial cancers. The MLH1 promoter was methylated in 41 of 53 (77%) MSI-positive cancers investigated. In MSI-negative tumors on the other hand, there was evidence for limited methylation in only one of 11 tumors studied. Immunohistochemical investigation of a subset of the tumors revealed that methylation of the MLH1 promoter in MSI-positive tumors was associated with loss of MLH1 expression. Immunohistochemistry proved that two MSI-positive tumors lacking MLH1 methylation failed to express the MSH2 mismatch repair gene. Both of these cancers came from women who had family and medical histories suggestive of inherited cancer susceptibility. These observations suggest that epigenetic changes in the MLH1 locus account for MSI in most cases of sporadic endometrial cancers and provide additional evidence that the MSH2 gene may contribute substantially to inherited forms of endometrial cancer. [ABSTRACT FROM AUTHOR]

Objective:To clarify the origin of defective mismatch repair (MMR) in sporadic endometrial cancers with microsatellite instability (MSI), a thorough mutation analysis was performed on the human mismatch repair gene MSH3.Methods:Twenty-eight MSI-positive endometrial cancers were investigated for mutations in the human mismatch repair gene MSH-3 using single-strand conformation variant (SSCV) analysis of all 24 exons. All variants were sequenced. Loss of heterozygosity was investigated at all MSH3 polymorphisms discovered. A subset of tumors were investigated for methylation of the 5′ promoter region of MSH3 using Southern blot hybridization.Results:An identical single-base deletion (ΔA) predicted to result in a truncated protein was discovered in six tumors (21.4%). This deletion occurs in a string of eight consecutive adenosine residues (A8). Because simple repeat sequences are unstable in cells with defective MMR, the observed mutation may be an effect, rather than a cause, of MSI. Evidence of inactivation of the second MSH3 allele in tumors with the ΔA mutation would strongly support a causal role for these MSH3 mutations. However, there was no evidence of a second mutation, loss of sequences, or methylation of the promoter region in any of the tumors with the ΔA mutation.Conclusion: Although the ΔA mutation is a frequent event in sporadic MSI-positive endometrial cancers, it may not be causally associated with defective DNA MMR. [ABSTRACT FROM PUBLISHER]

ABSTRACT Tumors with defective mismatch repair acquire large numbers of strand slippage mutations including frameshifts in coding sequence repeats. We identified a mutational hotspot, p.T204fs, in the insulator-binding protein ( CTCF) in MSI-positive endometrial cancers. Although CTCF was described as a significantly mutated gene by the endometrial cancer TCGA, the A7 track variants leading to T204 frameshifts were not reported. Reanalysis of TCGA data using Pindel revealed frequent T204fs mutations, confirming CTCF is an MSI target gene and revealed the same frameshifts in tumors with intact mismatch repair. We show that T204fs transcripts are subject to nonsense-mediated decay and as such, T204fs mutations are unlikely to act as dominant negatives. The spectrum and pattern of mutations observed is consistent with CTCF acting as a haploinsufficient tumor suppressor. [ABSTRACT FROM AUTHOR]