Correlation of the presence and extent of loss of heterozygosity mutations with histological classifications of Barrett’s esophagus

BMC Gastroenterology

Sydney Finkelstein²  Dennis M Smith²  Shyam J Thakkar¹  Sara A Jackson²  Eric Ellsworth² 

[1] West Penn Allegheny Health System, Division of Gastroenterology, Pittsburgh, PA, USA;RedPath Integrated Pathology, Inc, 2515 Liberty Ave, Pittsburgh, PA, 15222, USA

关键词: Genomic instability;    Tumor suppressor gene mutation;    Clonal expansion;    Loss of heterozygosity;    Allelic imbalance;    High grade dysplasia;    Low grade dysplasia;    Indefinite for dysplasia;    Intestinal metaplasia;    Barrett’s esophagus;   

Others  :  858258
DOI  :  10.1186/1471-230X-12-181

 received in 2012-09-14, accepted in 2012-12-18,  发布年份 2012

【 摘 要 】

Background

Recent advances in the management of Barrett’s Esophagus (BE) have placed greater emphasis on accurate diagnosis of BE as well as better prediction of risk for progression to esophageal adenocarcinoma (EAC). Histological evaluation of BE is particularly challenging with significant inter-observer variability. We explored the presence and extent of genomic instability in BE biopsy specimens as a means to add supplementary information to the histological classification and clinical decision-making related to early disease.

Methods

We reviewed histology slides from 271 patients known to have BE. Using histological features as a guide, we microdissected target cell populations with various histological classifications of BE (intestinal metaplasia, “indefinite for dysplasia”, low grade dysplasia, or high grade dysplasia). DNA was extracted from microdissected targets and analyzed for loss of heterozygosity (LOH) using a panel of 16 LOH mutational markers associated with tumor suppressor genes at chromosomal loci 1p, 3p, 5q, 9p, 10q, 17p, 17q, 18q, 21q, 22q. The presence or absence of mutations and the clonality of each mutation were determined for each marker.

Results

The presence and clonal expansion of LOH mutations was formulated into mutational load (ML) for each microdissected target analyzed. ML correlated with the histological classification of microdissected targets, with increasingly severe histology having higher ML. Three levels of mutation load (no ML, low ML, and high ML) were defined based on the population of microdissected targets histologically classified as intestinal metaplasia. All microdissected targets with dysplasia had mutations, with a high ML consistently present in high grade dysplasia targets. Microdissected targets histologically classified as intestinal metaplasia or “indefinite for dysplasia” spanned a range of no, low, and high ML.

Conclusions

The results of this study reinforce the association of genomic instability with disease progression in BE. The presence and extent (clonality) of genomic instability, as assessed by mutational load, may assist histology in defining early stages of BE that are potentially at greater risk for disease progression. Assessment of mutational load using our panel of LOH mutational markers may be a useful adjunct to microscopic inspection of biopsy specimens, and thereby, improve patient management.

【 授权许可】

   
2012 Ellsworth et al.; licensee BioMed Central Ltd.

【 图 表 】

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