Correlation of Mutational Change with Histological Disease Progression in Barrett's Esophagus
Georgios Deftereos, Christina Narick, Jan F Silverman, Lindsay L Freed, Eric MG Ellsworth, Sara A Jackson, Sydney D Finkelstein. Allegheny General Hospital, Pittsburgh, PA; RedPath Integrated Pathology, Inc., Pittsburgh, PA
Background: Barrett's Esophagus (BE) is a pre-cancerous condition that can progress to low grade dysplasia (LGD) and/or high grade dysplasia (HGD) and ultimately to adenocarcinoma. Current BE classification is based on microscopic features. Although mutations are fundamental to disease progression, the role of mutational analysis to help better classify and characterize BE remains unclear.
Design: Formalin-fixed, paraffin-embedded gastroesophageal biopsy/resection specimens from 42 patients were examined. From those, 89 targets representing areas histologically diagnosed as intestinal metaplasia (IM), LGD, HGD and carcinoma (CA) were microdissected and examined for loss of heterozygosity (LOH) and microsatellite instability (MSI) using PCR/capillary electrophoresis. A panel of 22 DNA markers at 10 different genomic loci was tested. The frequency which mutations occurred at each genomic locus for each histology was determined.
Results: The percentage of targets with mutations at each locus generally increased with progressively worse histology. In targets diagnosed as CA, nearly all loci examined were mutated in ≥ 50% of targets (Table). Mutations of TP53 (17p) and CDNK2A (9p), known to play in important role in progression of BE to cancer, were among the most frequently detected in IM, but were always accompanied by other mutations in LGD/HGD. Of note, the size of chromosomal deletion as well as evidence of MSI increased in relationship to progressive level of dysplasia.
Conclusions: Using a panel of genomic loci readily detects mutations associated with HGD and CA. Many of the loci were also frequently mutated in LGD and IM, suggesting that these mutations begin to accumulate early during BE and may play a role in driving the morphological changes associated with disease progression. Various patterns of molecular change are increasingly more evident from dysplasia to carcinoma, including deletion size and microsatellite instability. Analyzing patterns of molecular changes that correlate with histologic stages of disease progression may add an additional dimension to the microscopic evaluation of BE.
Monday, March 4, 2013 1:00 PM
Poster Session II # 112, Monday Afternoon