Endometrial cancer, arising in the lining of the uterus, is the most common gynecologic malignancy in the US, with an estimated 39,080 new cases and 7,400 deaths in 2007 (American Cancer Society statistics). For reasons that are not fully understood, African-American women with endometrial cancer have a significantly poorer survival than Caucasian women. While this likely reflects multiple causes, including differences in access to healthcare, a recent study of controlled clinical trials noted that African-American women with late stage endometrial cancer had lower survival rates than Caucasian women, even when administered similar treatments. This suggests that differences in tumor biology or genetics might also contribute to the documented racial disparity in survival from endometrial cancer. We are currently studying clinically aggressive subtypes of endometrial cancer (type II disease), from both African-American and Caucasian women, to search for genetic alterations that lead to the development of these tumors. ? ? Aim 1: To validate and extend previously reported genetic alterations within type II endometrial tumors ? To date, most studies of type II endometrial cancer have analyzed only a very limited number of candidate cancer genes from a small number of tumors. Consequently, a high degree of variability in the frequency of genetic alterations has been noted between studies.
We aim to reanalyze all genes previously implicated in endometrial tumorigenesis within a larger series of type II endometrial tumors. Overall, this investigation will provide extended insight into the genes and pathways that are disrupted during the development of type II endometrial cancer, in both the African-American and Caucasian populations, and may highlight functional genetic pathways for more detailed evaluation in future studies.? ? Aim 2: To identify molecular therapeutic targets for type II endometrial cancer? Small molecule inhibitors of tyrosine kinases constitute a relatively new class of drug some of which have proven to be effective in treating cancer patients whose tumors have sustained an activating mutation within the target kinase. The goal of this study is to determine whether any of the 90 known tyrosine kinase encoding genes are mutated within type II endometrial tumors, from both African-Americans and Caucasians. If present, mutated kinases may define new molecular therapeutic targets for this disease, as well as further our understanding of the genes and pathways disrupted during tumor development. ? ? Aim 3: To determine whether mutations within the cohesin gene family underlie chromosomal instability in endometrial cancer? Many clinically aggressive endometrial tumors exhibit chromosome instability, manifested as aneuploidy, or changes in chromosome number. The genetic basis of aneuploidy in cancer is poorly understood. However, recent studies of colorectal cancer have indicated that mutations within a family of genes controlling sister chromatid cohesion may underlie aneuploidy in this tumor type.
The aim of this investigation is to determine whether mutations within the 23 known cohesin genes are associated with aneuploidy in endometrial cancer from both African-Americans and Caucasians. If present, mutated cohesin genes might serve as potential drug targets that could be considered for future therapeutic intervention.? ? Progress: During the past year we have established a bank of 85 type II endometrial tumors, representing 18 African American and 67 Caucasian cases, as well as matched normal control tissue for each case. We are continuously expanding this resource by prospectively collecting additional tumors through collaborators and the Cooperative Human Tissue Network (NCI). To date, 35 tumors have been reviewed pathologically by my collaborator (Dr. Maria Merino) to independently confirm their histology and identify regions of tissue with high tumor cell content suitable for DNA isolation. Genetic investigations during the past year have been conducted on this subset of tumors. To date we have identified somatic mutations within the cancer causing genes, KRAS, P53, PIK3CA, PTEN, in accordance with published literature. However, we have not observed mutations within the BRAF kinase-encoding gene in type II disease, in contrast with published reports. Our search for mutations within tyrosine kinase-encoding genes is underway, in collaboration with the NIH Intramural Sequencing Center (NISC). This is a multistage project and, to date, approximately half of the kinase-encoding genes have been sequenced from 15 tumors. Likewise, the large-scale sequence analysis of the cohesin gene family has been designed in collaboration with NISC and the analysis is ongoing. Preliminary investigations of the CDC4 cohesin gene, within my own laboratory, have revealed inactivating mutations within 14% of type II endometrial tumors (5 of 35 cases). Although CDC4 mutations have been reported previously in endometrial cancer, no distinction was made between their occurrence by disease subtype. Therefore our early data provide novel insights into the role of CDC4 perturbations in clinically aggressive forms of endometrial cancer. We are currently extending our analyses of these, and other cancer-causing genes within the same functional genetic pathways, to all 85 tumors, to gain further insights into the precise frequency and spectrum of mutations within these genes in type II endometrial cancer in both African American and Caucasian women.
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