Chromosomal Instability in Barrett's Esophagus Is Related to Telomere Shortening

Finley, Jennifer C.; Reid, Brian J.; Odze, Robert D.; Sanchez, Carissa A.; Galipeau, Patricia C.; Li, Xiaohong; Self, Steven G.; Gollahon, Katherine A.; Blount, Patricia L.; Rabinovitch, Peter S.

doi:10.1158/1055-9965.epi-05-0837

Cited by 58 publications

(61 citation statements)

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“…Telomere dysfunction is also associated with bone marrow failure (50), specifically MGUS and multiple myeloma (51,52). Very short telomeres are also associated with CLL (53), dyskeratosis congenita (54), pancreatic cancer (55), prostate cancer (9), and Barrett's esophagus, which is associated with an increased risk of esophageal adenocarcinoma (56). These data suggest that the alteration of telomeres is potentially an important tool for cancer diagnostics for a broad range of tumors.…”

Section: Discussionmentioning

confidence: 99%

Novel automated three‐dimensional genome scanning based on the nuclear architecture of telomeres

Klewes

Höbsch

Katzir³

et al. 2010

Cytometry Pt A

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Telomeres, the end of chromosomes, are organized in a nonoverlapping fashion and form microterritories in nuclei of normal cells. Previous studies have shown that normal and tumor cell nuclei differ in their 3D telomeric organization. The differences include a change in the spatial organization of the telomeres, in telomere numbers and sizes and in the presence of telomeric aggregates. Previous attempts to identify the above parameters of 3D telomere organization were semi-automated. Here we describe the automation of 3D scanning for telomere signatures in interphase nuclei based on three-dimensional fluorescent in situ hybridization (3D-FISH) and, for the first time, define its sensitivity in tumor cell detection. The data were acquired with a highthroughput scanning/acquisition system that allows to measure cells and acquire 3D images of nuclei at high resolution with 403 or 603 oil and at a speed of 10,000-15,000 cells h 21 , depending on the cell density on the slides. The automated scanning, TeloScan, is suitable for large series of samples and sample sizes. We define the sensitivity of this automation for tumor cell detection. The data output includes 3D telomere positions, numbers of telomeric aggregates, telomere numbers, and telomere signal intensities. We were able to detect one aberrant cell in 1,000 normal cells. In conclusions, we are able to detect tumor cells based on 3D architectural profiles of the genome. This new tool could, in the future, assist in patient diagnosis, in the detection of minimal residual disease, in the analysis of treatment response and in treatment decisions. '

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Section: Discussionmentioning

confidence: 99%

Novel automated three‐dimensional genome scanning based on the nuclear architecture of telomeres

Klewes

Höbsch

Katzir³

et al. 2010

Cytometry Pt A

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“…T here have been ver y few re por ts of specific aneusomies in esophageal premalignant lesions; using FISH, some studies showed hyperdiploidy involving chromosomes 4 and 8 in BE, aneuploidy in chromosome 11 in esophageal tumors and Barrett's dysplasias [20][21][22][23] . In the present work, all the precancerous lesions including BE with high-grade dysplasia exhibited aneusomy of chromosome 11.…”

Section: Discussionmentioning

confidence: 99%

Chromosome 11 aneusomy in esophageal cancers and precancerous lesions- an early event in neoplastic transformation: An interphase fluorescencein situhybridization study from south India

Mohan

Ponnala²,

Reddy³

et al. 2007

WJG

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which may play a role in the neoplastic transformation of esophageal precancerous lesions to cancers. INTRODUCTIONMore than 30% of the adult population exhibits upper gastrointestinal tract disorders associated with symptoms such as regurgitation, heartburn and dysphagia, warranting an endoscopic evaluation. Some of these esophageal pathologies require medication while others can be managed by altering life-style and dietary habits. A certain percentage of these, however, progress into esophageal malignancies. In India, esophageal cancer is the second leading cancer in men and fourth leading cancer in women [1] . Epithelial tumors of the esophagus [squamous cell carcinoma (SCC) and adenocarcinoma (ADC)] are responsible for more than 95% of all esophageal carcinomas. This malignancy presents generally as a locally advanced disease, hence leading to poor prognosis with an average 5-year survival of < 12% in India [2] . Abnormal proliferation of the esophageal epithelial cells with hyperplasia and dysplasia in the normal squamous lining are regarded as premalignant lesions [3,4] . Another common premalignant condition is Barrett's esophagus (BE), where patients have a forty-fold increased risk for developing adenocarcinoma as compared to normal individuals. Although significant advances have been made in the diagnosis and treatment of esophageal carcinomas, not many studies have evaluated markers in the target tissue, in association with increased risk for malignant Abstract AIM: To detect aneusomic changes with respect to chromosome 11 copy number in esophageal precancers and cancers wherein the generation of cancer-specific phenotypes is believed to be associated with specific chromosomal aneuploidies. METHODS:We p e r fo r m e d f l u o r e s c e n c e i n s i t u hybridization (FISH) on esophageal tissue paraffin sections to analyze changes in chromosome 11 copy number using apotome-generated images by optical sectioning microscopy. Sections were prepared from esophageal tumor tissue, tissues showing preneoplastic changes and histologically normal tissues (control) obtained from patients referred to the clinic for endoscopic evaluation. RESULTS:Our results demonstrated that aneusomy was seen in all the cancers and preneoplastic tissues, while none of the controls showed aneusomic cells. There was no increase in aneusomy from precancers to cancers. CONCLUSION:Our results suggest that evaluation of chromosome 11 aneusomy in esophageal tissue using FISH with an appropriate signal capture-analysis system, can be used as an ancillary molecular marker predictive of early neoplastic changes. Future studies can be directed towards the genes on chromosome 11,

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“…Short telomeres have also been found in biopsies taken from Barrett's esophagus, a pre-neoplastic state that precedes esophageal adenocarcinoma. Barrett's esophagus samples with the shortest telomeres also had the highest degree of chromosomal abnormalities (Finley et al, 2006). As a result, it is currently believed that many if not most cancers arise from cells in which telomere erosion has provoked a 'crisis' beyond which telomerase expression had to be reinstated (or alternative telomere maintenance mechanisms had to be activated) to immortalize the cells (Sahin and Depinho, 2010).…”

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confidence: 99%

“…Tetraploidization has been observed in the early stages of colorectal (Danes, 1978), breast (Dutrillaux et al, 1991), cervical cancer (Olaharski et al, 2006) as well as in Barrett's esophagus (Finley et al, 2006). Although the natural history of tetraploidy in human cancers has not been thoroughly investigated, in vitro results indicate that the inactivation of p53 is permissive for tetraploidization (because p53-sufficient cells usually die from apoptosis as they become tetraploid) (Castedo et al, 2006;Senovilla et al, 2009; Figure 1).…”

mentioning

confidence: 99%

“…Although the natural history of tetraploidy in human cancers has not been thoroughly investigated, in vitro results indicate that the inactivation of p53 is permissive for tetraploidization (because p53-sufficient cells usually die from apoptosis as they become tetraploid) (Castedo et al, 2006;Senovilla et al, 2009; Figure 1). Accordingly, the loss of p53 function is associated with tetraploidy in Barett's esophagus (Finley et al, 2006) and in early cervical cancers (Skyldberg et al, 1999). Tetraploidy constitutes a metastable state because tetraploid cells tend to lose chromosomes progressively during aberrant dipolar mitoses (Ganem and Pellman, 2007) and/or undergo multipolar mitosis during which chromosomes are distributed among the daughter cells in a near-to-random manner (Roumier et al, 2005;Vitale et al, 2010).…”

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confidence: 99%

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A novel source of tetraploid cancer cell precursors: telomere insufficiency links aging to oncogenesis

2010

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Epithelial cancers of the elderly are caused by a combination of telomere dysfunction and the mutational invalidation of major tumor suppressors including p53. A recent article published in Cell by Davoli et al. shows that the simultaneous elimination of p53 and telomerase causes a state of chronic DNA damage that results in tetraploidization through endoreplication, that is, two consecutive S phases that are not separated by mitosis. As tetraploid cells represent a metastable intermediate between normal diploidy and cancer-associated aneuploidy, this novel route to tetraploidization may constitute (one of) the functional link(s) between aging and carcinogenesis.

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Chromosomal Instability in Barrett's Esophagus Is Related to Telomere Shortening

Cited by 58 publications

References 50 publications

Novel automated three‐dimensional genome scanning based on the nuclear architecture of telomeres

Novel automated three‐dimensional genome scanning based on the nuclear architecture of telomeres

Chromosome 11 aneusomy in esophageal cancers and precancerous lesions- an early event in neoplastic transformation: An interphase fluorescencein situhybridization study from south India

A novel source of tetraploid cancer cell precursors: telomere insufficiency links aging to oncogenesis

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