Abundant expression of the intestinal protein villin in Barrett's metaplasia and esophageal adenocarcinomas

Villin is a cytoskeletal protein that is involved in the formation of brush-border microvilli in normal small intestine and colon epithelium. This protein is present in Barrett's metaplasia but is reported not to be expressed in Barrett's adenocarcinoma. In this study, we analyzed villin protein expression in Barrett's metaplasia and in both Barrett's adenocarcinomas and tumors of the gastric cardia. Immunohistochemical analysis was used to evaluate the expression and cellular localization of the villin protein in 21 cases of Barrett's metaplasia, 30 cases of Barrett's adenocarcinoma, 16 cases of gastric cardia adenocarcinoma, and eight cases of adenocarcinoma of the distal esophagus. Southern, northern, and western blot analyses were used to evaluate the potential mechanisms for regulation of villin protein expression. Villin protein expression was observed in 21 of 21 cases (100%) of intestinal-type Barrett's metaplasia and in 28 of 30 cases (93%) of Barrett's adenocarcinoma and was thus highly expressed in these tumors. Northern blot analysis demonstrated villin mRNA (3.5 and 2.7 kb) in both villin-positive Barrett's metaplasia and adenocarcinomas. Western blot analysis with the antibody used for immunohistochemical analysis confirmed the presence of a single villin protein band of 95 kDa. Abundant villin expression also was present in both adenocarcinoma of the gastric cardia (13 of 16 cases; 81%) and distal esophageal adenocarcinomas of unknown origin (six of eight cases; 75%). The intestinal brush-border enzyme sucrase isomaltase was found to be present in only 22 of 46 cases (48%) of the adenocarcinomas that expressed villin. We concluded that the protein villin is highly expressed in Barrett's adenocarcinomas and is well maintained in these and other esophageal tumors. Mol. Carcinog. 22:182–189, 1998. © 1998 Wiley-Liss, Inc.     

Numerical aberration and point mutation of p53 gene in human gastric intestinal metaplasia and well-differentiated adenocarcinoma: Analysis by fluorescence in situ hybridization (FISH) and PCR-SSCP

This study examined p53 gene alterations in human gastric mucosa, intestinal metaplasia and well-differentiated (cohesive type) adenocarcinomas to clarify to the role of the p53 gene in gastric tumorigenesis by means of fluorescence in situ hybridization (FISH), polymerase-chain-reaction-single-strand-conformation polymorphism (PCR-SSCP) and immunohistochemistry. Gene alterations were compared with numerical changes of chromosome 17. Samples were obtained from 31 surgically resected stomachs affected with gastric cancer. There was no nuclear p53 protein in cells from normal gastric mucosa. Among 23 specimens of intestinal metaplasia, cells with p53 protein were variably detected in 5 incomplete metaplasias (colonic type). A histological study revealed a mildly dysplastic appearance. PCR-SSCP identified p53-gene mutation in exons 5 and 8 in 2 of the 5 samples. Numerical aberrations of chromosome 17 and the p53 gene were undetectable both in normal mucosa and in intestinal metaplasia. Variable numbers of tumor cells contained p53 protein in 13 (54%) of 24 carcinomas, and PCR-SSCP revealed abnormal bands in 5 of them. Mutations were detected in exons, 5, 7, 7, 7 and 8. FISH analysis demonstrated that 6 carcinomas emitted 3 or 4 signals for chromosome 17, and 7 gave one signal for the p53 gene in over 20% of the cells. Ten (77%) of 13 carcinomas examined by FISH appeared to show a p53-gene deletion. © 1996 Wiley-Liss, Inc.     

Distal chromosome 17q loss in Barrett's esophageal and gastric cardia adenocarcinomas: Implications for tumorigenesis

The molecular genetic mechanisms underlying esophageal cancer are poorly understood. However, a novel gene that may be involved in esophageal carcinogenesis was recently localized by others to distal 17q by linkage analysis of kindreds with palmoplantar keratoderma and squamous cell carcinoma of the esophagus. To help determine whether a distal 17q gene may also be involved in the pathogenesis of primary Barrett's esophageal and gastric cardia adenocarcinomas, we performed loss of heterozygosity (LOH) analysis of 21 Barrett's and 18 gastric cardia adenocarcinomas at loci spanning 17q: cen—BRCA1—SSTR2—D17S2058—D17S929—D17S722—D17S937—D17S802—tel. Over 50% of the Barrett's and cardia adenocarcinomas demonstrated loss of an allele at one or more informative distal 17q markers. One common overlapping region of loss involved loci mapped to distal 17q24–proximal 17q25, which tentatively defines a potential chromosomal region distal to BRCA1 involved in the pathogenesis or progression of both types of adenocarcinomas. LOH analysis of DNA from matched microdissected sections of Barrett's metaplasia suggested that loss of D17S2058 in this region may be an early event in the malignant transformation of Barrett's metaplasia. No statistically significant correlations between 17q LOH and tumor stage or patient survival were noted. In summary, LOH mapping of 17q in Barrett's and cardia adenocarcinomas suggests the existence of at least one putative distal 17q tumor suppressor gene involved in the pathogenesis of these tumors. Mol. Carcinog. 22:222–228, 1998. © 1998 Wiley-Liss, Inc.     

Comparison of p53 and DNA content abnormalities in adenocarcinoma of the oesophagus and gastric cardia.

This study examined the association between 17p allelic loss, p53 gene mutation, p53 protein expression and DNA aneuploidy in a series of adenocarcinomas arising in the oesophagus and gastric cardia. 17p allelic loss was detected in 79% (15 of 19) of oesophageal and in 83% (29 of 35) of gastric adenocarcinomas. p53 mutations were detected in 70% (14 of 20) and 63% (26 of 41) of oesophageal and of gastric adenocarcinomas respectively. Both tumour types were associated with a predominance of base transitions at CpG dinucleotides. In five cases of oesophageal adenocarcinoma, the same mutation was detected both in tumour and in adjacent dysplastic Barrett''s epithelium. Diffuse p53 protein expression was detected in 65% (13 of 20) and 59% (24 of 41) of oesophageal and of gastric tumours, respectively, and was associated with the presence of p53 missense mutation (Chi-squared, P < 0.0001). DNA aneuploidy was detected in 80% (16 of 20) of oesophageal and in 70% (28 of 40) of gastric tumours. No association was found between p53 or DNA content abnormalities and tumour stage or histological subtype. In conclusion, this study detected a similar pattern of p53 alterations in adenocarcinoma of the oesophagus and gastric cardia--molecular data consistent with the observation that these tumours demonstrate similar clinical and epidemiological features.     

Expression of p16, cyclin D<Subscript>1</Subscript> and RB protein in gastric carcinoma and premalignant lesions

Objective: To investigate the expression of p16, cyclin D₁ and Rb protein in gastric carcinoma and premalignant lesions including dysplastic gastric mucosa and intestinal metaplasia gastric mucosa. Methods: Using SP immunohistochemical methods, the expression of p16, cyclin D1 and Rb proteins was detected in 10 specimens of normal gastric mucosa, 15 specimens of dysplastic gastric mucosa, 15 specimens of intestinal metaplasia gastric mucosa, 30 specimens of gastric carcinoma. The clinical characteristics of the 30 patients with gastric carcinoma were analysed to explore the relationship between the parameter detected and biological action of gastric cancer. Results: Expression of p16 protein was detected in 90% of normal gastric mucosa, 86.67% of dysplastic gastric mucosa, 86.67% of intestinal metaplasia gastric mucosa, 36.67% of gastric carcinoma. The positive rate of p16 protein expression in gastric carcinoma is significantly lower than that in normal gastric mucosa and gastric premalignant lesions mucosa (P<0.01). Expression of cyclin D₁ protein was detected in 10% of normal gastric mucosa, 20% of dysplastic gastric mucosa, 20% of intestinal metaplasia gastric mucosa, 53.33% of gastric carcinoma. The positive rate of cyclin D₁, protein expression in gastric carcinoma is significantly higher than that in normal gastric mucosa and gastric premalignant lesions mucosa (P<0.05). Expression of Rb protein was detected in 90% of normal gastric mucosa, 80% of dysplastic gastric mucosa, 80% of intestinal metaplasia gastric mucosa, 50% of gastric carcinoma. The positive rate of Rb protein expression in gastric carcinoma is significantly lower than that in normal gastric mucosa (P<0.05). The expression of p16, cyclin D₁ gene were associated with the degree of differentiation of gastric carcinoma, lymphnodes metastasis and distant metastasis. Conclusion: p16, Cyclin D₁ and Rb gene play important role in gastric carcinoma genesis. The expression of p16, cyclin D₁ and Rb gene have some value to the diagnosis at earlier stage of gastric cancer. Detection of expression of p16, cyclin D₁ gene would be helpful to judge the prognosis of gastric cancer. Biography: MIAO Lin (1966–), male, master of medicine, associate professor, Second Affiliated Hospital, Nanjing Medical University, majors in gastroenterological cancer.     

p53 mutations in the non-neoplastic mucosa of the human stomach showing intestinal metaplasia

In order to ascertain whether genetic alterations occur during the early stages of gastric carcinogenesis, abnormal accumulation of p53 protein and mutation of its gene in stomach tissue showing intestinal metaplasia were investigated using immunohistochemistry and polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Immunohistochemistry detected 19 foci showing nuclear accumulation of p53 protein in non-neoplastic gastric mucosa in a total of 756 sections (477 of which contained intestinal metaplasia) from 16 resected stomachs containing gastric adenocarcinomas. Of these 19 p53-positive foci, 17 were diagnosed histologically as incomplete-type intestinal metaplasia and 2 as pseudopyloric glands in the regenerative mucosa. Furthermore, 14 such foci were detected in 6 patients with multiple gastric cancers. No correlation between high-iron diamine (HID)-positive sulfomucin production and p53-positive glands was observed. The DNAs were extracted selectively from these p53-positive metaplastic glands and examined for p53 mutations by PCR-SSCP analysis followed by direct sequencing. In only 10 lesions could exons 5 to 8 be investigated completely, and of these, 4 were shown to possess p53 mutations, which were on exon 5 in 3 cases and on exon 7 in 1 case. These results indicate that irreversible genetic changes had already occurred in morphologically non-neoplastic gastric mucosa with intestinal metaplasia, and are consistent with the hypothesis that intestinal metaplasia, especially the incomplete type, may contain precursor lesions of gastric cancer. © 1996 Wiley-Liss, Inc.     

EXPRESSION OF p16,CYCLIN D1 AND RB PROTEIN IN GASTRIC CARCINOMA AND PREMALIGNANT LESIONS

Gastric carcinoma is one of the most serious diseases in mankind. Its pathogenesis has not been understood very clearly. Recent researches suggested that oncogenes (such as cyclin D1), antioncogenes (ie., p16, Rb) and cell cycle played an important role in the pathogenesis of gastric carcinoma. But there are few reports about the relationship between these genes in gastric carcinoma and gastric premalignant lesions. In this study, we will discuss these problems. MATERIALS AND METHO…     

CDX2 hox gene product in a rat model of esophageal cancer

Background

Barrett''s mucosa is the precursor of esophageal adenocarcinoma. The molecular mechanisms behind Barrett''s carcinogenesis are largely unknown. Experimental models of longstanding esophageal reflux of duodenal-gastric contents may provide important information on the biological sequence of the Barrett''s oncogenesis.

Methods

The expression of CDX2 hox-gene product was assessed in a rat model of Barrett''s carcinogenesis. Seventy-four rats underwent esophago-jejunostomy with gastric preservation. Excluding perisurgical deaths, the animals were sacrificed at various times after the surgical treatment (Group A: <10 weeks; Group B: 10–30 weeks; Group C: >30 weeks).

Results

No Cdx2 expression was detected in either squamous epithelia of the proximal esophagus or squamous cell carcinomas. De novo Cdx2 expression was consistently documented in the proliferative zone of the squamous epithelium close to reflux ulcers (Group A: 68%; Group B: 64%; Group C: 80%), multilayered epithelium and intestinal metaplasia (Group A: 9%; Group B: 41%; Group C: 60%), and esophageal adenocarcinomas (Group B: 36%; Group C: 35%). A trend for increasing overall Cdx2 expression was documented during the course of the experiment (p = 0.001).

Conclusion

De novo expression of Cdx2 is an early event in the spectrum of the lesions induced by experimental gastro-esophageal reflux and should be considered as a key step in the morphogenesis of esophageal adenocarcinoma.     

Amplification and over-expression of the EGFR and erbB-2 genes in human esophageal adenocarcinomas

Esophageal cancer is one of the 10 most prevalent human cancers worldwide. The incidence of esophageal adenocarcinoma is on the rise and patients with this disease typically have very poor prognosis. Informative biomarkers would benefit the clinical management of this disease. We examined 13 cases with esophageal adenocarcinomas and 5 cases with Barrett's esophagus for amplification of the EGFR and erbB-2 genes. We detected multiple copies of the EGFR gene in 30.8% of the tumors and multiple copies of the erbB-2 gene in 15.4% of the tumors. Of the cases with amplification of the erbB-2 gene, co-amplification of the EGFR gene was found. Multiple copies of the EGFR gene were also found in one case of Barrett's esophagus. Immunohistochemical staining of the tissues revealed increased expression of the erbB-2 protein in Barrett's mucosa and adenocarcinoma, but no associations between staining intensity and degree of EGFR or erbB-2 gene amplification, histology, or tumor stage were found. Differential polymerase chain reaction was examined as a method for pre-operative detection of gene amplification in esophageal tumors and Barrett's mucosa.     

Malignant transformation of foveolar hyperplastic polyp of the stomach: a histopathological study

The author investigated histopathology of malignant changes of gastric foveolar hyperplastic polyps (GFHP). A total of 497 GFHP from 412 patients were retrospectively examined. Malignant changes were present in 11 GHP (2.2%). They were focal malignancies and well-differentiated adenocarcinoma without apparent invasion. In all the 11 GFHP, dysplastic glands were present in the vicinity of carcinomatous foci. Focal intestinal metaplasia was recognized in one case and was absent in the remaining 10 GFHP. Focal dysplastic glands were recognized in 51 GFHP (10%). Of these, four GFHP were associated with focal intestinal metaplasia, but the remaining 47 GFHP were not associated with intestinal metaplasia. Intestinal metaplasia alone was recognized in 23 GFHP (5%). Immunohistochemically, all carcinomatous foci within the 11 GFHP with malignant transformation showed positive p53 expression and high Ki-67 labeling. Of the 51 GFHP with dysplasia, 42 GFHP were positive for p53 protein, and the remaining 9 GFHP were negative for p53 protein. The dysplastic lesions of the 51 GFHP showed relatively high Ki-67 index. Intestinal metaplasia within GFHP was negative for p53 protein and showed low Ki-67 labeling. These results suggest that malignant transformation of GFHP may occur in 2.2% of cases, and that malignant changes develop via hyperplasia–dysplasia–carcinoma sequence in GFHP. Intestinal metaplasia within GFHP was not associated with carcinogenesis of GFHP.     

Helicobacter pylori induces caudal‐type homeobox protein 2 and cyclooxygenase 2 expression by modulating microRNAs in esophageal epithelial cells

Dysregulation of microRNAs (miRNAs) has been linked to virulence factors of Helicobacter pylori. The role of H. pylori in esophageal disease has not been clearly defined. We previously reported that H. pylori esophageal colonization promotes the incidence of Barrett's esophagus and esophageal adenocarcinoma in vivo. Here, we studied the direct effects of H. pylori on the transformation of esophageal epithelial cells, with particular focus on whether H. pylori exerts its effects by modulating miRNAs and their downstream target genes. The normal human esophageal cell line HET‐1A was chronically exposed to H. pylori extract and/or acidified deoxycholic acid for up to 36 weeks. The miRNA profiles of the esophageal epithelial cells associated with H. pylori infection were determined by microarray analysis. We found that chronic H. pylori exposure promoted acidified deoxycholic acid‐induced morphological changes in HET‐1A cells, along with aberrant overexpression of intestinal metaplasia markers and tumorigenic factors, including caudal‐type homeobox protein 2 (CDX2), mucin 2, and cyclooxygenase 2 (COX2). Helicobacter pylori modified the miRNA profiles of esophageal epithelial cells, particularly aberrant silencing of miR‐212‐3p and miR‐361‐3p. Moreover, in biopsies from Barrett's esophagus patients, esophageal H. pylori colonization was associated with a significant decrease in miR‐212‐3p and miR‐361‐3p expression. Furthermore, we identified COX2 as a target of miR‐212‐3p, and CDX2 as a target of miR‐361‐3p. Helicobacter pylori infection of esophageal epithelial cells was associated with miRNA‐mediated upregulation of oncoprotein CDX2 and COX2. Our observations provide new evidence about the molecular mechanisms underlying the association between H. pylori infection and esophageal carcinogenesis.     

Association of transforming growth factor alpha (TGFA) and its precursors with malignant change in Barrett's epithelium: Biological and clinical variables

Adenocarcinomas of the gastro-esophageal junction (GEJ) and those arising in Barrett's esophagus (BE) are increasing in the West and have a poorer prognosis than distal stomach cancers. This has been attributed mainly to anatomical location, but biological factors such as growth-regulatory molecules have been implicated. We have investigated the expression of one of these factors, TGFα, and its precursor prepro TGFα in 82 adenocarcinomas of GEJ (32 resected specimens and 50 biopsies) as well as in 48 BE biopsies without tumor, by immunohis-tochemistry and by Western-blot analysis. TGFα staining was shown in the cytoplasm and membrane of cells. Western blot confirmed that most immunoreactivity was against mature TGFa (5.6 kDa), but higher-molecular-weight bands were also identifiable, suggesting some reactivity with prepro protein. TGFα expression was more extense and intense in intestinal metaplasia and cancer. The tubular histological type of adenocarcinoma was more often positive than the signet-ring type. Primary tumors with lymph-node metastases also had increased TGFα expression. We conclude, therefore, that there is differential regulation of the expression of TGFα and its precursors during esophageal tumorigenesis. © 1995 Wiley-Liss, Inc.     

Analysis of Ki-67, p53 and Bcl-2 expression in the dysplasia-carcinoma sequence of Barrett's esophagus.

The grading of dysplasia in Barrett's esophagus has prognostic importance, however observer variation limits the reliability of simple histological analysis alone. We investigated Ki-67, p53 and Bcl-2 expression in Barrett's esophagus, in the sequence from Barrett's low-grade dysplasia to high-grade dysplasia and infiltrating adenocarcinoma. Forty-four esophagectomy specimens were utilized: 39 specimens with esophageal dysplasia and adenocarcinoma and 5 specimens with esophageal dysplasia only. This gave 83 sections (2 sections for specimens with dyplasia and carcinoma) examined from 44 patients. The sections were examined for Ki-67, p53 and Bcl-2 reactivity by immunohistochemistry. Low-grade dysplasia was present in 14 sections, high-grade dysplasia in 30 sections and carcinoma in 39 sections. Ki-67 expression occurred in 2 out of 14 (14%) sections with low-grade dysplasia, in 22 out of 30 (73%) sections with high-grade dysplasia and in 34 out of 39 (87%) sections with carcinoma (p<0.001). p53 protein expression was found in 1 of 14 (7%) sections with low-grade dysplasia, in 18 of 30 (60%) sections with high-grade dysplasia and in 33 of 39 (85%) sections with carcinoma (p<0.001). Expression of Bcl-2 was found in 11 of 14 (84%) sections with low-grade dysplasia but immunoreactivity was not seen in any section with high-grade dysplasia or Barrett's carcinoma. Our results indicate that overexpression of Ki-67, Bcl-2 protein and p53 mutations can be identified as early events during neoplastic progression in Barrett's esophagus. These data support the hypothesis that, in the progression of Barrett's metaplasia to adenocarcinoma, the balance of proliferation/apoptosis plays an important role.     

Over-expression of p53 protein in gastric adenoma and cancer

Recently, alterations of p53 gene in gastric cancer have been reported by several authors, but the role of p53-gene alterations in early step of carcinogenesis of gastric cancer remains unclear. To assess whether p53 expression is an early event in the carcinogenesis of gastric cancer, 402 gastric tumors (14 hyperplastic polyps, 48 gastric adenomas, 340 gastric cancers) were analyzed by immunohistochemistry using the specific antibody, PAb1801, against p53 oncoprotein. Five (15%) of 34 adenomas and 110 (32%) of 340 gastric cancers showed a definite positive nuclear staning for p53 protein. In contrast, the anti-p53 MAb did not show any specific staining in normal gastric epithelial cells, intestinal metaplasia or hyperplastic polyps. Out of nine adenomas showing mild dysplasia, only one tumor (11%) showed p53 expression. In contrast, 4 (16%) of 25 adenomas showing moderate dysplasia revealed positive p53 expression. In addition, positive p53 staining was not found in adenomas less than 1 cm in diameter, but five (25%) of 20 adenomas 1 cm or more in diameter showed definite p53-staining. In this way, the positive-p53 tissue status in adenomas was correlated with the dysplastic grade and size of adenomas. The incidence of positive-p53 immunoreaction in the differentiated type of cancers was 35% and showed no relation to wall invasion. On the contrary, p53 expression in the undifferentiated type of m-cancers, in which tumor invasion was limited to the mucosal layers, was detected in only one (5%) of 21 cases. Among undifferentiated type of gastric cancer, however, deeply invasive cancers showed higher p53-positive rate, as compared with m-cancer. These results may suggest p53 gene activation at a relatively early stage of the adenoma-carcinoma sequence, leading to the development of some differentiated adenocarcinomas in the stomach.     

Columnar metaplasia in a surgical mouse model of gastro‐esophageal reflux disease is not derived from bone marrow‐derived cell

The incidence of esophageal adenocarcinoma has increased in the last 25 years. Columnar metaplasia in Barrett's mucosa is assumed to be a precancerous lesion for esophageal adenocarcinoma. However, the induction process of Barrett's mucosa is still unknown. To analyze the induction of esophageal columnar metaplasia, we established a mouse gastro‐esophageal reflux disease (GERD) model with associated development of columnar metaplasia in the esophagus. C57BL/6 mice received side‐to‐side anastomosis of the esophagogastric junction with the jejunum, and mice were killed 10, 20, and 40 weeks after operation. To analyze the contribution of bone marrow‐derived cells to columnar metaplasia in this surgical GERD model, some mice were transplanted with GFP‐marked bone marrow after the operation. Seventy‐three percent of the mice (16/22) showed thickened mucosa in esophagus and 41% of mice (9/22) developed columnar metaplasia 40 weeks after the operation with a mortality rate of 4%. Bone marrow‐derived cells were not detected in columnar metaplastic epithelia. However, scattered epithelial cells in the thickened squamous epithelia in regions of esophagitis did show bone marrow derivation. The results demonstrate that reflux induced by esophago‐jejunostomy in mice leads to the development of columnar metaplasia in the esophagus. However, bone marrow‐derived cells do not contribute directly to columnar metaplasia in this mouse model.     

P53 expression in esophageal dysplasia - a possible biomarker for carcinogenesis of esophageal squamous-cell carcinoma

The tumor suppressor gene product p53 has been detected in a high percentage of esophageal squamous cell carcinoma. To evaluate the role of this protein in carcinogenesis, we examined the p53 overexpression both in esophageal dysplasia and in esophageal squamous cell carcinoma in the same patients. Using anti-p53 antibodies pAb1801 and CM-1, we analyzed immunohistochemically 36 dysplastic lesions from 36 patients with esophageal cancer. Nuclear p53 was detected in 14 of 36 dysplasias (39%). From mild to moderate to severe dysplasia, p53 positivity showed tendency to increase in number. Seventeen of the 36 squamous cell carcinomas showed p53 expression (47%). There was a significant concurrent p53 expression in esophageal dysplasia and its related squamous cell carcinoma (p=0.00345). These results indicate that p53 mutation is closely associated with the initiation of this cancer.     

High-resolution genomic alterations in Barrett's metaplasia of patients who progress to esophageal dysplasia and adenocarcinoma

The main risk factor for esophageal dysplasia and adenocarcinoma (DAC) is Barrett's esophagus (BE), characterized by intestinal metaplasia. The critical genomic mechanisms that lead to progression of nondysplastic BE to DAC remain poorly understood and require analyses of longitudinal patient cohorts and high-resolution assays. We tested BE tissues from 74 patients, including 42 nonprogressors from two separate groups of 21 patients each and 32 progressors (16 in a longitudinal cohort before DAC/preprogression-BE and 16 with temporally concurrent but spatially separate DAC/concurrent-BE). We interrogated genome-wide somatic copy number alterations (SCNAs) at the exon level with high-resolution SNP arrays in DNA from formalin-fixed samples histologically confirmed as nondysplastic BE. The most frequent abnormalities were SCNAs involving FHIT exon 5, CDKN2A/B or both in 88% longitudinal BE progressors to DAC vs. 24% in both nonprogressor groups (p = 0.0004). Deletions in other genomic regions were found in 56% of preprogression-BE but only in one nonprogressor-BE (p = 0.0004). SCNAs involving FHIT exon 5 and CDKN2A/B were also frequently detected in BE temporally concurrent with DAC. TP53 losses were detected in concurrent-BE but not earlier in preprogression-BE tissues of patients who developed DAC. CDKN2A/p16 immunohistochemistry showed significant loss of expression in BE of progressors vs. nonprogressors, supporting the genomic data. Our data suggest a role for CDKN2A/B and FHIT in early progression of BE to dysplasia and adenocarcinoma that warrants future mechanistic research. Alterations in CDKN2A/B and FHIT by high-resolution assays may serve as biomarkers of increased risk of progression to DAC when detected in BE tissues.     

Intestinal metaplasia of the stomach. I: Quantitative analysis in gastric peptic ulcer and in incipient adenocarcinoma in Japanese subjects

A novel method of quantitation of the extent of intestinal metaplasia (IM) was applied to 50 resected stomachs from Japanese subjects; 25 with peptic gastric ulcer, 25 with incipient adenocarcinoma. The total length of the IM was significantly larger (p less than 0.05) in incipient adenocarcinomas than in peptic ulcers; the total length of the gastric mucosa analyzed being similar in the two groups. The intestinal metaplasia index (IMI; i.e. the ratio between IM and the length of the gastric mucosa analyzed) in incipient adenocarcinomas was significantly higher (p less than 0.05) than in gastric ulcers. In incipient adenocarcinomas, the IMI decreased significantly (p. less than 0.001) from lesser towards greater curvature. In peptic ulcers, the decrease was less abrupt. In 12 of the 25 specimens, the incipient adenocarcinoma was classified as intestinal type, and in the remaining 13 specimens as diffuse type. The total length of the IM was significantly larger (p less than 0.01) in specimens with intestinal type adenocarcinoma than in specimens with diffuse type; the total length of the gastric mucosa investigated being similar in the two groups. The IMI was significantly higher (p less than 0.01) in specimens containing intestinal type adenocarcinoma as compared to those with diffuse type adenocarcinoma. This was valid for the lesser curvature, for the mucosa adjacent to the lesser curvature, and for the mucosa by the greater curvature. From the results, it is apparent that intestinal metaplasia is a widely occurring phenomenon not only in specimens with intestinal type incipient adenocarcinoma or with diffuse type incipient adenocarcinoma, but also with benign peptic ulcer. The difference resides in that the metaplastic mucosa is more universally distributed in specimens with incipient intestinal adenocarcinomas (provided that longitudinal mucosal areas are considered in the comparison). The quantitative method herein reported will be applied in the future to compare the extent and distribution of intestinal metaplasia in gastric specimens from various geographical regions having disparate incidences of gastric ulcers and carcinomas.     

p53 correlates with improved survival in patients with esophageal adenocarcinoma

Esophageal adenocarcinoma is a virulent malignancy that is rapidly increasing in incidence. Overexpression of p53, a tumor-suppressor gene with prognostic significance in many malignancies, has not been adequately evaluated in this disease. The purpose of this study was to evaluate the pattern and importance of p53 protein accumulation in patients with esophageal adenocarcinoma. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded tissue from 24 patients, all of whom had early stage disease. Nineteen of 24 patients underwent surgery, and 16 had complete tumor resection. p53 oncoprotein immuno-reactivity was demonstrated in 50% (12/24) of patients overall and 50% (8/16) of patients undergoing esophagectomy. p53 overexpression was more common in patients with well-differentiated tumors (P=0.07). The tissue surrounding tumor stained positive for p53 in six patients, four of whom had no evidence of Barrett's epithelium. Among the 16 patients who underwent esophagectomy, those whose tumors demonstrated p53 overexpression had a longer overall (28 vs. 13.5 months) and disease-free (24.3 vs. 13 months) median survival. The difference in disease-free survival was significant (P=0.05). Our findings suggest that p53 overexpression may serve as a marker of improved survival in patients with esophageal adenocarcinoma. © 1995 Wiley-Liss, Inc.