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A novel surveillance method for Barrett’s esophagus patients in a North Holland region by DNA FISH for detection of genetic abnormalities in brush cytology specimens.

Projectomschrijving

Een Barrett-slokdarm ontstaat door het terugstromen van maagzuur in de slokdarm. Het slijmvlies onderaan de slokdarm verandert daardoor. Barret-patiënten hebben een verhoogde kans op slokdarmkanker en krijgen regelmatig een endoscopisch onderzoek. De resultaten van dit onderzoek zijn echter niet zo betrouwbaar. Dit project onderzoekt een andere methode: de FISH DNA-test. Daarmee worden fouten in het erfelijk materiaal (genetische afwijkingen) opgespoord. Als er ‘hoogrisico’-afwijkingen worden gevonden, kan de patiënt vaker worden gecontroleerd. Patiënten zonder hoogrisico-afwijkingen hoeven dan minder vaak voor controle te komen. Het onderzoek wordt uitgevoerd bij Barrett-patiënten in Noord-Holland.
Het onderzoek wijst uit dat de FISH-test een goede voorspellende waarde heeft, en daarmee de screening kan verbeteren. De definitieve resutaten van het onderzoek worden eind 2012 verwacht.

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Samenvatting van de aanvraag

Barrett’s esophagus (BE) is a metaplastic premalignant condition of the distal esophagus, which is a consequence of gastro esophageal reflux disease (GERD). In Western European countries, the incidence and prevalence of BE is increasing, estimated to be 1-2% (1; 2; 3). BE is primarily found in Caucasians, with a 2 to 3 times higher incidence in males (3). The rising incidence of BE is due to a growing number of patients with GERD, which in turn is associated with Western Lifestyle and increasing obesity (4-6). Since BE is the precursor lesion of the highly malignant esophageal adenocarcinoma (EAC), the recognition of BE is highly relevant (7-9). In the Netherlands (3; 5), as in most Western countries, the incidence of EAC is the most rapidly increasing of all malignancies (10; 11). EAC is an aggressive malignancy, with an overall 5 yrs survival of <20%. Yet, when detected at early stage, long term survival may improve up to 95% (12; 13). Since progression of BE into EAC is characterized by histopathological changes, classified as low grade (LGD) and high grade dysplasia (HGD), routine surveillance programs of BE patients aim at screening for these histological changes. It seems, however, that screening for histological changes alone is not efficient, nor reliable, for identifying BE patients at risk. Of importance is that progression of BE into EAC is associated with the occurrence of several genetic changes. It is anticipated that assessing these molecular changes may serve as biomarkers, which may lead to improve the efficiency of the current screening programs (14). DNA Fluorescent in situ hybridization (FISH) is a molecular tool that can efficiently detect genetic abnormalities in patient tissues. In preclinical exploratory studies, we evaluated diverse panels of DNA FISH probes for detecting several genetic abnormalities in brush cytology specimens of BE patients (15-17). Two informative FISH marker sets were defined; one set that is ‘potentially prognostic’ for development of dysplasia (15), while the second is ‘diagnostic’ for detecting high grade dysplasia or EAC (16). By combining the sets, finally a ‘potentially prognostic/diagnostic’ FISH probe set was defined consisting of six DNA probes, which are specific for chromosomes 7, 17, the locus specific regions of p53 (17p13.1), p16 (9p21), Her-2 (17q11.2-12) and c-myc (8q24.12). We subsequently validated an automated method for scoring the FISH results on cytology specimens, and herewith developed a novel assay for screening BE patients. Between 2002 and 2004, this automated FISH assay was applied to evaluate the whole Barrett cohort of the AMC for the six biomarkers (15). Here, this assay will be further validated for its clinical value by also including a large unselected BE cohort in the Amsterdam/North Holland region for analysis in longitudinal and prospective follow up studies. AIMS/PLAN 1. To screen a BE population (N=250) of six regional hospitals in the Amsterdam/North Holland region by using the automated FISH assay and the combined diagnostic/prognostic DNA FISH marker set, consisting of centromeric DNA probes specific for chromosome 7, 17, and the locus specific probes for p53 (17p13.1), p16(9p21), Her-2(17q11.2-12) and c-myc (8q24.12-13), for determining the true frequencies of these biomarkers in an unselected cohort of BE patients. 2. To evaluate the biomarkers specific for Chromosome 7, 17, p53 (17p13.1) and p16 (9p21) for their ‘potentially prognostic value’ in this unselected BE cohort. Hereto, the frequency of the prognostic markers will be evaluated with respect to increasing dysplasia as determined by histological and cytological evaluation in biopsy and cytological specimens. 3. To evaluate the biomarkers specific for Chromosome 7, 17, Her-2 (17q11.2-12), c-myc (8q24.12) for their true ‘diagnostic value’ in the unselected BE cohort. Hereto, the sensitivity and specificity for detecting high grade dysplasia and/or EAC will be determined. 4. To create a large BE cohort (N=400) by combining this cohort (n=250) with the AMC population (n=150) for testing the ‘true predictive value’ of the prognostic set after a mean follow up period of at least 2 years. EXPECTED RESULTS We anticipate that the novel screening assay that is based on automated assessment of a set of molecular biomarkers will have been validated for the surveillance of cohorts of unselected BE patients. In the long run, this improved secondary prevention measure may lead to a prolonged overall life expectancy with better quality of life of patients that are at risk for developing esophageal adenocarcinoma. Future studies will aim at evaluating this assay for its cost/benefit and implementation on a larger scale in the Netherlands.

Onderwerpen

Kenmerken

Projectnummer:
120520015
Looptijd: 100%
Looptijd: 100 %
2008
2011
Onderdeel van programma:
Projectleider en penvoerder:
Prof. dr. K.K. Krishnadath
Verantwoordelijke organisatie:
Amsterdam UMC - locatie AMC