Antonia Sepulveda, M.D., Ph.D.

Description of Research Expertise

Research Interests: Dr. Antonia Sepulveda's research laboratory is centered on studies of gastrointestinal carcinomas arising in a setting of infectious and inflammatory conditions. Basic bench research and translational research are conducted in the laboratory.
Research Description: Our laboratory group has two funded research programs. Our goals are to characterize the underlying molecular mechanisms of progression to cancer and the identification of molecular diagnostic tests for gastrointestinal dysplasia and carcinomas. Current projects in the laboratory include:
1. H. Pylori Induced Epigenetic Alterations, Mutagenesis and Altered DNA Repair in Gastric Carcinogenesis
Our studies have identified novel molecular mechanisms through which H. pylori bacteria lead to altered molecular programs in the stomach epithelial lining that may result in increased risk of stomach cancer in susceptible patients. We discovered that H. pylori bacteria-induced molecular changes lead to mutations in the genome of epithelial cells. These observations provide the basis for a new paradigm in cancer development, highlighting the importance of host cell-bacterial interaction in cancers where bacteria may play a role as carcinogens.
Sub-projects:
a) To identify the fundamental mechanisms underlying the reduced levels of MLH1 and MSH2 proteins and MSI-type mutations induced by H. pylori in cultured gastric epithelial cells.
b) To characterize the effects of H. pylori gastritis on DNA mismatch repair deficiency and mutagenesis in the stomach mucosa in vivo.
c) To identify critical and diagnostic genes affected by epigenetic CpG methylation during gastritis, atrophy, dysplasia and gastric cancer.
d) To determine the role of microRNAs in H. pylori associated gastric carcinogenesis.
e) To identify genes affected by epigenetic CpG methylation during gastritis, dysplasia and gastric cancer, in mouse models of H. pylori gastric neoplasia.
2. Epigenetic Markers of Neoplasia in Inflammatory Bowel Disease (IBD).
This project involves the characterization of specific methylation patterns by quantitative methylation specific PCR of selected gene panels for diagnosis of dysplasia and cancer in ulcerative colitis. Our studies led to the identification of novel CpG methylation markers of colonic adenomas and carcinomas, applicable to neoplasia arising in patients with IBD as well as in sporadic colorectal adenomas and adenocarcinomas.
Sub-projects:
a) Determination of cut-off values of CpG methylation by SYBR green real-time PCR for each of seven CpG methylation markers that best correlate with pathological diagnosis (dysplasia vs. cancer vs. colitis).
b) Topographic mapping of CpG methylation will be performed by examining multiple biopsy sites (non-neoplastic colon; dysplasia, cancer or indeterminate dysplasia; and biopsies from mucosa near the lesions). The panel of CpG methylation markers is hoped to help in the pathological diagnosis of dysplasia and cancer and may indicate whether a patient’s colon is at risk of developing dysplasia by examining colitis biopsies, such as those obtained by flexible sigmoidoscopy, potentially reducing the frequency of required surveillance colonoscopy.
c) To determine whether the CpG methylation of novel CpG markers can differentiate between hyperplastic polyps, serrated adenomas and traditional colonic adenomas.
3. Clinical applications of microsatellite instability and mismatch repair analysis in hereditary cancers (colorectal, gastric, and endometrial cancer).
Research Laboratory Address:
218 John Morgan Bldg.
3620 Hamilton Walk
Philadelphia, PA 19104-6082
Telephone: 215-746-1908

Description of Clinical Expertise

Gastrointestinal Pathology and Molecular Pathology
Director of Surgical Pathology, Hospital of the University of Pennsylvania
Director Surgical Pathology Fellowship, Hospital of the University of Pennsylvania