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1.  Aberrant Vimentin Methylation Is Characteristic of Upper Gastrointestinal Pathologies 
We have previously established aberrant DNA methylation of Vimentin exon-1 (VIM methylation) as a common epigenetic event in colon cancer and as a biomarker for detecting colon neoplasia. We now examine VIM methylation in neoplasia of the upper gastrointestinal tract.
Using a quantitative real-time Methylation-Specific PCR assay we tested for VIM methylation in archival specimens of esophageal and gastric neoplasia.
We find that acquisition of aberrant VIM methylation is highly common in these neoplasms, but largely absent in controls. The highest frequency of VIM methylation was detected in lesions of the distal esophagus, including 91% of Barrett’s esophagus (BE, n=11), 100% of high grade dysplasia (HGD, n=5), and 81% of esophageal adenocarcinoma (EAC, n=26), but absent in controls (n=9). VIM methylation similarly was detected in 87% of signet ring (n=15) and 53% of intestinal type gastric cancers (n=17). Moreover, in tests of cytology brushings VIM methylation proved detectable in 100% of BE cases (n=7), 100% of HGD cases (n=4), and 83% of EAC cases (n=18), but was absent in all controls (n=5).
These findings establish aberrant VIM methylation as a highly common epigenetic alteration in neoplasia of the upper gastrointestinal tract, and demonstrate that Barrett’s esophagus, even without dysplasia, already contains epigenetic alterations characteristic of adenocarcinoma.
These findings suggest VIM methylation as a biomarker of upper gastrointestinal neoplasia with potential for development as molecular cytology in esophageal screening.
PMCID: PMC3454489  PMID: 22315367
Barrett’s Esophagus; Esophageal Cancer; Gastric Cancer; Vimentin; Methylation
2.  Variation In Age At Cancer Diagnosis In Familial Versus Non-Familial Barrett’s Esophagus 
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 non-familial (no affected relatives), duplex (two affected relatives), and multiplex (three or more affected relatives) FBE kindreds.
The study included 830 non-familial, 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 to duplex and non-familial kindreds (57 vs. 62 vs. 63 yrs, respectively, p = 0.0448). Mean body mass index (BMI) 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 to non-familial 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.
PMCID: PMC3275661  PMID: 22178570
Esophageal adenocarcinoma; Barrett’s esophagus; genetics; family history
3.  A Predictive Genetic Signature for Response to Fluoropyrimidine-Based Neoadjuvant Chemoradiation in Clinical Stage II and III Rectal Cancer 
Frontiers in Oncology  2013;3:288.
Purpose: Pre-operative chemoradiation (CRT) is currently the standard of care for patients with clinical stage II and III rectal cancer but only about 45% of patients achieve tumor downstaging and <20% of patients achieve a pathologic complete response. Better methods to stratify patients according to potential neoadjuvant treatment response are needed. We used microarray analysis to identify a genetic signature that correlates with a pathological complete response (pCR) to neoadjuvant CRT. We performed a gene network analysis to identify potential signaling pathways involved in determining response to neoadjuvant treatment.
Patients and Methods: We identified 31 T3–4 N0–1 rectal cancer patients who were treated with neoadjuvant fluorouracil-based CRT. Eight patients were identified to have achieved a pCR to treatment while 23 patients did not. mRNA expression was analyzed using cDNA microarrays. The correlation between mRNA expression and pCR from pre-treatment tumor biopsies was determined. Gene network analysis was performed for the genes represented by the predictive signature.
Results: A genetic signature represented by expression levels of the three genes EHBP1, STAT1, and GAPDH was found to correlate with a pCR to neoadjuvant treatment. The difference in expression levels between patients who achieved a pCR and those who did not was greatest for EHBP1. Gene network analysis showed that the three genes can be connected by the gene ubiquitin C (UBC).
Conclusion: This study identifies a 3-gene signature expressed in pre-treatment tumor biopsies that correlates with a pCR to neoadjuvant CRT in patients with clinical stage II and III rectal cancer. These three genes can be connected by the gene UBC, suggesting that ubiquitination is a molecular mechanism involved in determining response to treatment. Validating this genetic signature in a larger number of patients is proposed.
PMCID: PMC3839295  PMID: 24324931
rectal neoplasms; ubiquitination; gene array; UBC; EHBP1
4.  DNA methylation profiling in Barrett's esophagus and esophageal adenocarcinoma reveals unique methylation signatures and molecular subclasses 
Epigenetics  2011;6(12):1403-1412.
Barrett's esophagus (BE) is a metaplastic process whereby the normal stratified, squamous esophageal epithelium is replaced by specialized intestinal epithelium. Barrett's is the only accepted precursor lesion for esophageal adenocarcinoma (EAC), a solid tumor that is rapidly increasing in incidence in western countries. BE evolves into EAC through intermediate steps that involve increasing degrees of dysplasia. Current histologic criteria are quite subjective and the clinical behavior of BE is highly variable and difficult to predict using these standards. It is widely believed that molecular alterations present in BE and EAC will provide more precise prognostic and predictive markers for these conditions than the current clinical and histologic features in use. In order to further define molecular alterations that can classify unique groups of BE and EAC, we utilized methylation microarrays to compare the global gene methylation status of a collection of normal squamous, BE, BE + high-grade dysplasia (HGD), and EAC cases. We found distinct global methylation signatures, as well as differential methylation of specific genes, that discriminated these histological groups. We also noted high and low methylation epigenotypes among the BE and EAC cases. Additional validation of those CpG sites that distinguished BE from BE + HGD and EAC may lead to the discovery of useful biomarkers with potential clinical applications in the diagnosis and prognosis of BE and EAC.
PMCID: PMC3256330  PMID: 22139570
Barrett's esophagus; esophageal adenocarcinoma; DNA methylation; methylation microarray
5.  A Segregation Analysis of Barrett’s Esophagus and Associated Adenocarcinomas 
Familial aggregation of esophageal adenocarcinomas, esophagogastric junction adenocarcinomas, and their precursor Barrett’s esophagus has been termed Familial Barrett’s Esophagus (FBE). Numerous studies documenting increased familial risk for these diseases raise the hypothesis that there may be an inherited susceptibility to the development of BE and its associated cancers. In this study, using segregation analysis for a binary trait as implemented in S.A.G.E. 6.0.1, we analyzed data on 881singly ascertained pedigrees in order to determine whether FBE is caused by a common environmental or genetic agent and, if genetic, to identify the mode of inheritance of FBE. The inheritance models were compared by likelihood ratio tests and Akaike’s A Information Criterion. Results indicated that random environmental and/or multifactorial components were insufficient to fully explain the familial nature of FBE, but rather there is segregation of a major type transmitted from one generation to the next (p-value < 10−10). An incompletely dominant inheritance model together with a polygenic component fits the data best. For this dominant model, the estimated penetrance of the dominant allele is 0.1005 (95% confidence interval, CI: 0.0587 to 0.1667) and the sporadic rate is 0.0012 (95% CI: 0.0004 to 0.0042), corresponding to a relative risk of 82.53 (95% CI: 28.70 to 237.35), or odds ratio of 91.63 (95% CI: 32.01 to 262.29). This segregation analysis provides epidemiological evidence in support of one or more rare autosomally inherited dominant susceptibility allele(s) in FBE families, and hence motivates linkage analyses.
PMCID: PMC2838211  PMID: 20200424
familial esophageal adenocarcinomas; complex segregation analysis; dominant major gene inheritance; polygenic component; likelihood; AIC; unified model
6.  Image analysis for classification of dysplasia in Barrett’s esophagus using endoscopic optical coherence tomography 
Biomedical Optics Express  2010;1(3):825-847.
Barrett’s esophagus (BE) and associated adenocarcinoma have emerged as a major health care problem. Endoscopic optical coherence tomography is a microscopic sub-surface imaging technology that has been shown to differentiate tissue layers of the gastrointestinal wall and identify dysplasia in the mucosa, and is proposed as a surveillance tool to aid in management of BE. In this work a computer-aided diagnosis (CAD) system has been demonstrated for classification of dysplasia in Barrett’s esophagus using EOCT. The system is composed of four modules: region of interest segmentation, dysplasia-related image feature extraction, feature selection, and site classification and validation. Multiple feature extraction and classification methods were evaluated and the process of developing the CAD system is described in detail. Use of multiple EOCT images to classify a single site was also investigated. A total of 96 EOCT image-biopsy pairs (63 non-dysplastic, 26 low-grade and 7 high-grade dysplastic biopsy sites) from a previously described clinical study were analyzed using the CAD system, yielding an accuracy of 84% for classification of non-dysplastic vs. dysplastic BE tissue. The results motivate continued development of CAD to potentially enable EOCT surveillance of large surface areas of Barrett’s mucosa to identify dysplasia.
PMCID: PMC3018066  PMID: 21258512
(110.4500) Optical coherence tomography; (170.2150) Endoscopic imaging; (100.2960) Image analysis
7.  Assessment of Familiality, Obesity, and Other Risk Factors for Early Age of Cancer Diagnosis in Adenocarcinomas of the Esophagus and Gastro-esophageal Junction 
Adenocarcinomas of the esophagus and adenocarcinomas of the gastroesophageal junction are postulated to be complex genetic diseases. Combined influences of environmental factors and genetic susceptibility likely influence the age at which these cancers develop. The aim of this study was to determine whether familiality and other recognized risk factors are associated with the development of these cancers at an earlier age.
A structured validated questionnaire was utilized to collect self reported data on gastro-esophageal reflux symptoms, risk factors for Barrett’s esophagus (BE) and family history, including age of cancer diagnosis in affected relatives from probands with BE, adenocarcinoma of the esophagus, or adenocarcinoma of the gastro-esophageal junction, at five tertiary care academic hospitals. Medical records of all relatives reported to be affected were requested from hospitals providing this cancer care to confirm family histories. Familiality of BE/cancer, obesity (defined as body mass index > 30), gastro-esophageal reflux symptoms, and other risk factors were assessed for association with a young age of cancer diagnosis.
A total of 356, 216 non-familial and 140 familial, cancers were studied. The study population consisted of 292 (82%) men and 64 (18%) women. Mean age of cancer diagnosis was no different comparing familial and non-familial cancers, 62.6 yrs vs. 61.9 yrs, p = 0.70. There were also no significant differences in symptoms of gastroesophageal reflux, body mass index, race, gender, and smoking history between familial and non-familial cancers. Mean age of cancer diagnosis was significantly younger comparing those who were obese one year prior to diagnosis with those who were non-obese, mean age 58.99 yrs vs. 63.6 yrs, p = 0.008. Multivariable modeling of age at cancer diagnosis showed that obesity 1 year before diagnosis was associated with a younger age of cancer diagnosis (p=0.005) after adjustment for heartburn and regurgitation duration.
Obesity is associated with the development of esophageal and gastro-esophageal junctional adenocarcinomas at an earlier age. Familial cancers arise at the same age as non-familial cancers and have a similar risk factor profile.
PMCID: PMC2864226  PMID: 19491834
8.  The aberrant methylation of TSP1 suppresses TGF-β1 activation in colorectal cancer 
Colorectal cancer arises from the progressive accumulation of mutations and epigenetic alterations in colon epithelial cells. Such alterations often deregulate signaling pathways that affect the formation of colon cancer, such as the Wnt, RAS-MAPK and TGF-β pathways. The tumor promoting effects of mutations in genes, such as APC, have been demonstrated in cancer cell lines and in mouse models of intestinal cancer; however, the biological effects of most epigenetic events identified in colorectal cancer remain unknown. Consequently, we assessed whether the aberrant methylation of TSP1, the gene for thrombospondin 1, a regulator of TGF-β ligand activation, is an epigenetic mechanism for inhibiting the TGF-β signaling pathway. We found methylated TSP1 occurs in colon cancer cell lines (33%), colon adenomas (14%) and colon adenocarcinomas (21%). In primary colorectal cancers, loss of TSP1 expression correlated with impaired TGF-β signaling as indicated by decreased Smad2 phosphorylation and nuclear localization. Furthermore, methylation-induced silencing of TSP1 expression reduced the concentration of secreted active TGF-β1 and attenuated TGF-β signaling. Reversal of TSP1 methylation resulted in increased TSP1 mediated activation of the latent LAP:TGF-β complex and subsequent TGF-β receptor activation. Our results demonstrate that the aberrant methylation of TSP1 has biological consequences and provide evidence that the aberrant methylation of TSP1 is a novel epigenetic mechanism for suppressing TGF-β signaling in colorectal cancer.
PMCID: PMC2777657  PMID: 18425817
Thrombospondin; transforming growth factor β; methylation; colorectal cancer; epigenetics
9.  The Pathologist's Role in Rectal Cancer Patient Assessments 
Since Cuthbert Dukes fundamental work linking cancer stage to prognosis, the pathologist has had an ever-expanding role in the multidisciplinary management of rectal cancer. Gross dissection techniques and histologic evaluation are reviewed. The evolving tumor size, node status, metastasis classification (TNM) staging system is outlined. The pathologist's critical role in correctly assessing circumferential margins and establishing resection adequacy and staging accuracy via lymph node assessment is emphasized.
PMCID: PMC2789503  PMID: 20011197
Rectal cancer; total mesorectal excision; tumor size; node status; metastasis (TNM) classification; pathological evaluation

Results 1-9 (9)