Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation.

KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations.

Differential methylation hybridization array of endometrial cancers reveals two novel cancer-specific methylation markers.

Purpose: To identify novel endometrial cancer-specific methylation markers and to determine their association with clinicopathologic variables and survival outcomes.

Experimental Design: Differential methylation hybridization analysis (DMH) was done for 20 endometrioid endometrial cancers using normal endometrial DNA as a reference control. Combined bisulfite restriction analysis (COBRA) was used to verify methylation of sequences identified by DMH.

DNA repair pathway profiling and microsatellite instability in colorectal cancer.

Background: The ability to maintain DNA integrity is a critical cellular function. DNA repair is conducted by distinct pathways of genes, many of which are thought to be altered in colorectal cancer. However, there has been little characterization of these pathways in colorectal cancer.

Transcriptional profiling endometrial carcinomas microdissected from DES-treated mice identifies changes in gene expression associated with estrogenic tumor promotion.

Exposure to unopposed estrogen is a potent risk factor for developing human endometrial cancer. However, little is known about the transcriptional changes elicited by estrogens in endometrial carcinogenesis, in part, because of genetic and environmental heterogeneity of human tumors. We have begun to chart the expression signatures of endometrial tumors promoted with the synthetic estrogen, diethylstilbestrol (DES), in inbred mice.

Concordance of pharmacogenetic markers in germline and colorectal tumor DNA.

Introduction: Most cancer pharmacogenetic studies use germline DNA, as tumor tissue is often inaccessible in the advanced disease setting. However, this relies on the assumption that germline DNA is representative of the tumor genotype. To date, there has been little attention paid to defining the relationship between tumor and germline genomes.

Diethylstilbestrol effects and lymphomagenesis in Mlh1-deficient mice.

Inherited defects in DNA mismatch repair (MMR) predispose to a variety of malignancies in humans and in mouse knockout models. In humans, hemizygosity for one of several DNA MMR genes greatly increases an individual's risk for colon and endometrial carcinoma. Hemizygous mice develop gastrointestinal tumors at a low to moderate frequency.

RAS/RAF mutation and defective DNA mismatch repair in endometrial cancers.

Objective: Defective DNA mismatch repair is a common genetic abnormality in both colon cancers and endometrial cancers. Cancers with defective DNA mismatch repair have the so-called mutator phenotype and accumulate genetic errors at an increased rate. An early mutational target in cells with defect DNA mismatch repair may be the RAS/RAF pathway.

A panel of repeat markers for detection of microsatellite instability in murine tumors.

A substantial fraction of human malignancies lack functional DNA mismatch repair (MMR), accumulate mutations at high frequency, and exhibit microsatellite instability (MSI). In order to distinguish between MMR-competent and MMR-deficient malignancies, a consensus panel of microsatellite repeats has been adopted for MSI analysis of human tumors. There is no reference panel of repeats for MSI typing of murine malignancies.