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Variation in age at cancer diagnosis in familial versus nonfamilial Barrett's esophagus.

ABSTRACT: Genetic influences may be discerned in families that have multiple affected members and may manifest as an earlier age of cancer diagnosis. In this study, we determine whether cancers develop at an earlier age in multiplex Familial Barrett's Esophagus (FBE) kindreds, defined by 3 or more members affected by Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC).Information on BE/EAC risk factors and family history was collected from probands at eight tertiary care academic hospitals. Age of cancer diagnosis and other risk factors were compared between nonfamilial (no affected relatives), duplex (two affected relatives), and multiplex (three or more affected relatives) FBE kindreds.The study included 830 nonfamilial, 274 duplex, and 41 multiplex FBE kindreds with 274, 133, and 43 EAC and 566, 288, and 103 BE cases, respectively. Multivariable mixed models adjusting for familial correlations showed that multiplex kindreds were associated with a younger age of cancer diagnosis (P = 0.0186). Median age of cancer diagnosis was significantly younger in multiplex compared with duplex and nonfamilial kindreds (57 vs. 62 vs. 63 years, respectively, P = 0.0448). Mean body mass index was significantly lower in multiplex kindreds (P = 0.0033), as was smoking (P < 0.0001), and reported regurgitation (P = 0.0014).Members of multiplex FBE kindreds develop EAC at an earlier age compared with nonfamilial EAC cases. Multiplex kindreds do not have a higher proportion of common risk factors for EAC, suggesting that this aggregation might be related to a genetic factor.These findings indicate that efforts to identify susceptibility genes for BE and EAC will need to focus on multiplex kindreds.

SUBMITTER: Chak A

PROVIDER: S-EPMC3275661 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Variation in age at cancer diagnosis in familial versus nonfamilial Barrett's esophagus.

Chak Amitabh A Chen Yanwen Y Vengoechea Jaime J Canto Marcia I MI Elston Robert R Falk Gary W GW Grady William M WM Guda Kishore K Kinnard Margaret M Markowitz Sanford S Mittal Sumeet S Prasad Ganapathy G Shaheen Nicholas N Willis Joseph E JE Barnholtz-Sloan Jill S JS

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20111216 2

<h4>Background</h4>Genetic influences may be discerned in families that have multiple affected members and may manifest as an earlier age of cancer diagnosis. In this study, we determine whether cancers develop at an earlier age in multiplex Familial Barrett's Esophagus (FBE) kindreds, defined by 3 or more members affected by Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC).<h4>Methods</h4>Information on BE/EAC risk factors and family history was collected from probands at eight terti ...[more]

PMID: 22178570

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Project description:Background & aimsMicroRNA (miRNA) is highly stable in biospecimens and provides tissue-specific profiles, making it a useful biomarker of carcinogenesis. We aimed to discover a set of miRNAs that could accurately discriminate Barrett's esophagus (BE) from normal esophageal tissue and to test its diagnostic accuracy when applied to samples collected by a noninvasive esophageal cell sampling device.MethodsWe analyzed miRNA expression profiles of 2 independent sets of esophageal biopsy tissues collected during endoscopy from 38 patients with BE and 26 patients with normal esophagus (controls) using Agilent microarray and Nanostring nCounter assays. Consistently up-regulated miRNAs were quantified by real-time polymerase chain reaction in esophageal tissues collected by Cytosponge from patients with BE vs without BE. miRNAs were expressed from plasmids and antisense oligonucleotides were expressed in normal esophageal squamous cells; effects on proliferation and gene expression patterns were analyzed.ResultsWe identified 15 miRNAs that were significantly up-regulated in BE vs control tissues. Of these, 11 (MIR215, MIR194, MIR 192, MIR196a, MIR199b, MIR10a, MIR145, MIR181a, MIR30a, MIR7, and MIR199a) were validated in Cytosponge samples. The miRNAs with the greatest increases in BE tissues (7.9-fold increase in expression or more, P < .0001: MIR196a, MIR192, MIR194, and MIR215) each identified BE vs control tissues with area under the curve (AUC) values of 0.82 or more. We developed an optimized multivariable logistic regression model, based on expression levels of 6 miRNAs (MIR7, MIR30a, MIR181a, MIR192, MIR196a, and MIR199a), that identified patients with BE with an AUC value of 0.89, 86.2% sensitivity, and 91.6% specificity. Expression level of MIR192, MIR196a, MIR199a, combined that of trefoil factor 3, identified patients with BE with an AUC of 0.93, 93.1% sensitivity, and 93.7% specificity. Hypomethylation was observed in the promoter region of the highly up-regulated cluster MIR192-MIR194. Overexpression of these miRNAs in normal esophageal squamous cells increased their proliferation, via GRHL3 and PTEN signaling.ConclusionsIn analyses of miRNA expression patterns of BE vs non-BE tissues, we identified a profile that can identify Cytosponge samples from patients with BE with an AUC of 0.93. Expression of MIR194 is increased in BE samples via epigenetic mechanisms that might be involved in BE pathogenesis.

Dataset Information

Variation in age at cancer diagnosis in familial versus nonfamilial Barrett's esophagus.

Publications

Variation in age at cancer diagnosis in familial versus nonfamilial Barrett's esophagus.

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