Paul J. Goodfellow
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Ph.D.
Professor
Surgery
Genetics
Obstetrics and Gynecology
Molecular Genetics and Genomics Program
Human and Statistical Genetics Program
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Office Phone:
314-362-8106
Lab Phone:
314-362-2003
Other Phone:
314-362-2032
FAX:
314-362-8620
Box:
8109
Lab Address:
3350 Clinical Sciences Research Building
Email:
goodfellowp@wustl.edu
Keywords:
cancer; DNA; genetics; gene expression
Short Research Description:
Tumor initiation, oncogenes, DNA mismatch repair, human genetics, cancer.
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Research Abstract:
Our laboratory is investigating the genetic alterations that underlie development of uterine endometrial cancers. Endometrial cancer is the most common gynecologic malignancy in the United States. Like many cancers, uterine endometrial cancers are hormonally- responsive tumors. The genetic defects that are associated with the phenotypic progression from normal endometrium to carcinoma are elucidated through direct examination of primary human and mouse tumor tissues and precursor lesions. The lab’s efforts focus on the characterization of how changes in methylation of key regulatory sequences contribute to the cancer state, defining the inherited and acquired causes of defective DNA mismatch repair and determining how loss of DNA mismatch repair contributes to genotypic progression.
Endometrial, colon and other tumors with defective DNA mismatch repair accumulate large numbers of mutations. However, the genes that acquire mutations as a result of loss of mismatch repair remain elusive. We are attempting to determine how defective mismatch influences phenotypic and genotypic progression using a mouse model. Tumors are promoted with the synthetic estrogen, DES, in mice in which the Mlh1 DNA mismatch repair gene has been knocked out. Expression profiling in cancers and precancerous lesions provides candidate genes that are verified in mouse tumors, and their role in disease validated in human cancers. |
Selected Publications:
Buttin BM, Powell MA, Mutch DG, et al. Increased risk for HNPCC-associated synchronous and metachronous malignancies in patients with MSI-positive endometrial carcinoma lacking MLH1 promoter methylation. Clin Cancer Res 2004 10:481-490.
Buttin BM, Powell MA, Mutch DG, et al. Penetrance and expressivity of MSH6 germline mutations in seven kindreds not ascertained by family history. Am J Hum Genet 2004 74:1262-1269.
Goodfellow PJ, Buttin BM, Herzog TJ, et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci USA 2003 100:5908-5913.
Kabbarah O, Mallon MA, Pfeifer JD, et al. A panel of repeat markers for detection of microsatellite instability in murine tumors. Mol Carcinog 2003 38:155-159.
Kabbarah O, Pinto K, Mutch DG, Goodfellow PJ. Expression profiling of mouse endometrial cancers microdissected from ethanol-fixed, paraffin-embedded tissues. Am J Pathol 2003 165:755-762. |