National Human Genome Research Institute | National Institutes of Health U.S. Department of Health and Human Services |
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The goals of Dr. Bell's laboratory are to understand the genetic alterations that lead to clinically aggressive subtypes of endometrial cancer, to determine whether there is a heritable basis for familial endometrial cancer, and to uncover the genetic risk factors that promote the development of endometrial cancer at a young age. Endometrial cancer, which affects the endometrium (the lining of the uterus), is the most common gynecological malignancy in the United States. There are 41,200 new cases of endometrial cancer diagnosed each year, along with 7,350 deaths attributable to this disease. Most patients present with "type I" tumors with endometrioid histology and have a good prognosis, but around 15 percent are diagnosed with "type II" serous or clear cell tumors that are clinically aggressive. Patients with type II tumors have a five-year survival rate of less than 40 percent. Over the past few years, it has become evident that certain types of chromosomal and genetic alterations may be exploited as therapeutic targets in the treatment of certain malignancies. For example, the drug imatinib is highly effective in the treatment of chronic myelogenous leukemia with an underlying BCR-ABL chromosome translocation. Similarly, a subset of non-small cell lung cancers with specific mutations that affect the catalytic domain of the epidermal growth factor receptor (EGFR) responds to the drugs gefitinib and erlotinib. Dr. Bell aims to identify the genetic alterations that cause serous and clear cell tumors of the endometrium en route to developing new therapies for type II endometrial cancers. Towards that end, her research group is using high-density, single-nucleotide polymorphism (SNP) genotyping to identify genome-wide copy-number changes and loss-of-heterozygosity events in type II endometrial tumors. Parallel studies include extensive collaborations with the NIH Intramural Sequencing Center for performing mutational screens of all exons that encode the catalytic domains of 90 known tyrosine kinases. In addition, these efforts include searching for structural chromosomal alterations in endometrial tumors. Once specific genetic alterations are found to be associated with tumor development, more extensive examination of the clinicopathologic features of mutation-harboring tumors will be performed in an attempt to implicate individual genes or functional pathways that could be targeted for therapeutic intervention. An inherited susceptibility to endometrial cancer is usually associated with increased risk for hereditary non-polyposis colorectal cancer (HNPCC). In fact, endometrial cancer is the second most common form of malignancy diagnosed in women with HNPCC. Susceptibility to endometrial cancer is also associated with an increased risk for Cowden syndrome, which first produces symptoms in the late twenties and causes multiple noncancerous growths called hamartomas on the skin and mucous membranes. Cowden syndrome is also linked to the development of breast, thyroid, and endometrial malignancies. There are a few families that lack either the clinical manifestations or molecular characteristics of HNPCC or Cowden syndrome, yet still have a clustering of endometrial cancer cases, which suggests a tissue-specific etiology. It is possible that predisposition to endometrial cancer in these families is linked to one or more low-penetrance susceptibility alleles rather than a single, highly penetrant mutation. Dr. Bell brings valuable expertise to her studies of endometrial cancer. Previously, she discovered a cancer-susceptibility gene (CHEK2) that has been implicated in the development of breast and prostate cancer. She also defined the genetic alterations responsible for clinical sensitivity and resistance of lung cancer patients to the tyrosine kinase inhibitor gefitinib (Iressa); her group plans similar evaluations of the usefulness of potential therapies for type II endometrial cancer. Within the general population, women with an increased risk of developing endometrial cancer usually have an imbalance of estrogens and progesterones that are caused by one or more risk factors, including obesity, diabetes mellitus, polycystic ovary syndrome, early menarche, nulliparity and late menopause. Up to a quarter of endometrial cancer patients diagnosed before age 50 have one or more of these risk factors, but not all women with these risk factors develop endometrial cancer; thus, individual genetic variations appear to also affect disease susceptibility. To examine this phenomenon, Dr. Bell will perform case-control genetic association studies in order to establish what underlying genetic risk factors influence the development of endometrial cancer in premenopausal women, with the hope of making the predictive equation even more precise.
Last Reviewed: March 2, 2009 |
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