Correlation of the presence and extent of loss of heterozygosity mutations with histological classifications of Barrett's esophagus
Correlation of the presence and extent of loss of heterozygosity mutations with histological classifications of Barrett's esophagus
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DOI：
10.1186/1471-230x-12-181
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发表时间：
2012-12-27
影响因子：
2.4
通讯作者：
Finkelstein, Sydney
中科院分区：
文献类型：
--
作者：
Ellsworth, Eric;Jackson, Sara A.;Finkelstein, Sydney
背景资料：Barrett食管（BE）治疗的最新进展更加强调BE的准确诊断以及更好地预测进展为食管腺癌（EAC）的风险。BE的组织学评价尤其具有挑战性，观察者之间存在显著差异。我们探讨了BE活检标本中基因组不稳定性的存在和程度，作为一种手段，以补充信息的组织学分类和临床决策相关的早期diseases.Methods：我们回顾了271例已知有BE的组织学幻灯片。使用组织学特征作为指导，我们显微解剖了具有各种组织学分类的BE（肠化生、“不确定发育不良”、低度发育不良或高度发育不良）的靶细胞群。从显微切割的靶提取DNA，并使用一组与染色体位点1p、3p、5q、9p、10q、17p、17q、18q、21q、22q的肿瘤抑制基因相关的16个洛缺失突变标记分析杂合性缺失（洛）。突变的存在或不存在和每个突变的克隆性被确定为每个marker.Results：洛突变的存在和克隆扩展被配制成突变负荷（ML）为每个microdissected分析的目标。ML与显微解剖目标的组织学分类相关，组织学越严重，ML越高。根据组织学分类为肠化生的显微切割靶细胞群体，定义了三个突变负荷水平（无ML、低ML和高ML）。所有显微切割的异型增生靶点均存在突变，高级别异型增生靶点中始终存在高ML。显微解剖的目标组织学分类为肠上皮化生或“不确定的发育不良”跨越的范围内没有，低，高ML.Conclusions：这项研究的结果加强了BE的疾病进展与基因组不稳定性的关联。通过突变负荷评估的基因组不稳定性的存在和程度（克隆性）可能有助于组织学确定BE的早期阶段，这些阶段可能具有更大的疾病进展风险。使用我们的洛突变标志物评估突变负荷可能是活检标本显微镜检查的有用辅助手段，从而改善患者管理。
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.