Polymorphism/loss of heterozygosity of APC gene in GERD-Barrett's metaplasia-dysplasia-adenocarcinoma sequence

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Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego

Pol.Merkur Lekarski

May

155

385

389

LR: 20151119; JID: 9705469; 0 (Biomarkers, Tumor); ppublish

Poland

1426-9686; 1426-9686

PMID: 19606680

pol

English Abstract; Journal Article; IM

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19606680

The incidence of esophageal adenocarcinoma (ADC) has been increasing rapidly over the past few decades. Gastro-esopageal reflux disease (GERD), Barrett's esophagus (BE) and Barrett-associated dysplasia are a risk factor for esophageal cancer, but endoscopic surveillance have only a limited influence on cancer mortality. There is a great need to find molecular biomarkers predicting increased progression risk in GERD-Barrett's metaplasia-dysplasia-adenocarcinoma sequence to improve risk assessment and stratification of patients to surveillance program. AIM OF THE STUDY: To evaluate the polymorphism and prevalence of loss of heterozygosity (LOH) of APC tumor suppressor gene in mataplasia, dysplasia and adenocarcinoma. MATERIAL AND METHODS: In esophageal mucosal samples of 79 patients with: GERD (n=33), BE (n=27), BE+dysplasia (n=8) and ADC (n=11) we have studied LOH of APC tumor suppressor gene using PCR-restriction fragment length polymorphism (RFLP). A 133 bp fragment, spanning exon 11 of the APC gene was amplified, and Rsal digestion of the PCR product defined the alleles as either homozygous 133 bp (Rsa(-/-)) or 87 and 46 bp (Rsa(+/+)) fragments, and heterozygous (Rsa(+/-)) exhibiting the three fragments. Control peripheral blood cell DNA samples have been collected from 60 normal healthy subjects. RESULTS: Among 79 patients, there were 16 heterozygous (20%) for APC gene. In 16 informative heterozygous LOH was detected in 7 cases: 2/5 with GERD, 3/7--with BE, 1/2--with BE+dysplasia and 1/2--with ADC. There were no statistical differences between studied groups (NS). Distribution of the three alleles, Rsa(+/-), Rsa(+/+), and Rsa(-/-) was: 38, 47 and 15% in the healthy individuals, 25%, 25% and 50%--in GERD patients, 29%, 41% and 29%--in BE, 36%, 45% and 18% in BE+dysplasia and 25%, 67% and 8% in ADC patients, respectively. The frequency of heterozygous cases in control group was significantly higher than in patients group (p = 0.018), whereas Rsa (-/-) were the most frequent in patients group (p = 0.008). Rsa (-/-) were seen significantly more often in GERD compared to ADC patients (p = 0.005), in opposite to Rsa (+/+), which were significantly more frequent in ADC vs. GERD (p = 0.007). CONCLUSIONS: APC gene inactivation concerns minority of patients with esophageal adenocarcinoma, however, its detection indicates higher risk of progression to ADC. APC alternations appear to be early in GERD-BE-dysplasia-ADC sequence. The specific polymorphism may identify patients with high risk of progression into BE.

Adenocarcinoma/genetics/pathology, Adult, Aged, Barrett Esophagus/genetics/pathology, Biomarkers, Tumor/analysis, Disease Progression, Esophageal Neoplasms/genetics/pathology, Esophagus/pathology, Female, Gastric Mucosa/pathology, Gastroesophageal Reflux/genetics/pathology, Genes, APC, Heterozygote, Humans, Hyperplasia, Loss of Heterozygosity/genetics, Male, Metaplasia, Middle Aged, Polymorphism, Genetic, Precancerous Conditions/genetics

Mokrowiecka,A., Wierzchniewska-Lawska,A., Smolarz,B., Romanowicz-Makowska,H., Malecka-Panas,E.

Polimorfizm/utrata heterozygotycznosci genu APC w sekwencji GERD-przelyk barretta-dysplazja-rak gruczolowy przelyku

Department of Digestive Tract Diseases, Medical University of Lodz. anna.mokrowiecka@umed.lodz.pl

http://vp9py7xf3h.search.serialssolutions.com/?charset=utf-8&pmid=19606680

2009