Review Open Access
Copyright ©The Author(s) 2003. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 15, 2003; 9(6): 1156-1164
Published online Jun 15, 2003. doi: 10.3748/wjg.v9.i6.1156
Primary adenocarcinomas of lower esophagus, esophagogastric junction and gastric cardia: in special reference to China
Li-Dong Wang, Cancer Institute, Zhejiang University, Hangzhou 310009, Jiangsu Province, China and Laboratory for Cancer Research, College of Medicine, Zhengzhou University, Zhengzhou 450052, Henan Province, China
Shu Zheng, Cancer Institute, Zhejiang University, Hangzhou 310009, Jiangsu Province, China
Zuo-Yu Zheng, Laboratory for Cancer Research, College of Medicine, Zhengzhou University, Zhengzhou 450052, Henan Province, China
Alan G. Casson, Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada
Author contributions: All authors contributed equally to the work.
Supported by National Distinguished Young Scientist Foundation of China, No. 30025016 and Foundation of Henan Education Committee, No. 1999125
Correspondence to: Li-Dong Wang, M.D., Professor of Pathology and Oncology, Invited Profesor of Henan Province, Director fo Laboratory for Cancer Research, College of Medicine, Zhengzhou University, Zhengzhou, 450052, Henan Province, China.
Telephone: +86-371-6970165 Fax: +86-371-6970165
Received: May 20, 2003
Revised: June 4, 2003
Accepted: June 2, 2003
Published online: June 15, 2003


Gastric cardia adenocarcinoma (GCA) is an under-studied subject. The pathogenesis, molecular changes in the early stage of carcinogenesis and related risk factors have not been well characterized. There is evidence, however, that GCA differs from cancer of the rest of the stomach in terms of natural history and histopathogenesis. Adenocarcinomas of the lower esophagus, esophagogastric junction (EGJ) and gastric cardia have been given much attention because of their increasing incidences in the past decades, which is in striking contrast with the steady decrease in distal stomach adenocarcinoma. In China, epidemiologically, GCA shares very similar geographic distribution with esophageal squamous cell carcinoma (SCC), especially in Linzhou (formerly Linxian County), Henan Province, North China, the highest incidence area of esophageal SCC in the world. Historically, both GCA and SCC in these areas were referred to as esophageal cancer (EC) by the public because of the common syndrome of dysphagia. In Western countries, Barrett's esophagus is very common and has been considered as an important precancerous lesion of adenocarcinoma at EGJ. Because of the low incidence of Barrett's esophagus in China, it is unlikely to be an important factor in early stage of EGJ adenocarcinoma development. However, Z line up-growth into lower esophagus may be one of the characteristic changes in these areas in early stage of GCA development. Whether intestinal metaplasia (IM) is a premalignant lesion for GCA is still not clear. Higher frequency of IM observed at adjacent GCA tissues in Henan suggests the possibility of IM as a precancerous lesion for GCA in these areas. Molecular information on GCA, especially in early stage, is very limited. The accumulated data about the changes of tumor suppressor gene, such as p53 mutation, and ontogeny, such as C-erbB2, especially the similar alterations in GCA and SCC in the same patient, indicated that there might be some similar risk factors, such as nitrosamine, involved in both GCA and SCC in Henan population. The present observations also suggest that GCA should be considered as a distinct entity.


Adenocarcinomas of the gastric cardia are currently classified as gastric cancers[1,2]. However, recent studies have suggested that these tumors have distinct epidemiological and biological characteristics[3,4]. In the last two decades, the incidence of primary adenocarcinomas of the lower esophagus, esophagogastric junction (EGJ) and adenocarcinomas of the gastric cardia has increased dramatically in North America and Western European countries[3-6]. In contrast, the incidence of adenocarcinoma of the distal stomach has decreased steadily in recent years.

In China, adenocarcinomas of the gastric cardia have unique epidemiological features distinguishing these tumors from the adenocarcinomas of the distal stomach. Linzhou (formerly Linzhou County), the region with the highest incidence rate of esophageal cancer in the world, also has a high incidence of adenocarcinoma of the gastric cardia. However, the incidence of adenocarcinoma arising from the distal stomach is very low in this area. Therefore, previously, adenocarcinomas arising from the EGJ (gastric cardia) were referred to as esophageal cancers, because they shared similar clinical symptoms such as dysphagia. As most of the adenocarcinomas arising from the cardia are diagnosed at an advanced stage, it is very difficult to accurately define whether these tumors have a primary esophageal or gastric origin. Therefore, adenocarcinomas of the EGJ (gastric cardia) are now generally referred to as gastric cardia adenocarcinomas (GCA). With the exception of Barrett's esophagus (a well documented premalignant lesion of esophageal adenocarcinoma in Caucasians)[7,8], the role of other risk factors, such as H. pylori infection, diet, alcohol and tobacco exposure, still remains unclear.

Most studies of esophageal carcinoma in Linzhou have evaluated only esophageal squamous cell carcinoma (SCC). Few have studied adenocarcinoma (AC) of the gastric cardia, particularly as a separate pathological entity in China. In this review, recent epidemiological, histopathological and molecular biological advances were summarized to provide clues about the risk factors and the molecular carcinogenosis of adenocarcinomas of the lower esophagus, and EGJ (gastric cardia).


GCA shares several common features with the adenocarcinoma arising from the distal esophagus: a lower mean age of presentation, a higher incidence in the Caucasian population, a higher male to female ratio, and similar risk factors[4,9]. Epidemiological studies have demonstrated that smoking, alcohol consumption, increased body mass index (reflecting obesity), and lower socioeconomic status are risk factors for adenocarcinomas of both the distal esophagus and gastric cardia[10-12]. In Linzhou, China, adenocarcinoma of the gastric cardia was previously classified as esophageal cancer by the local registry for the past several decades, primarily because of comparable clinical features and similarity in therapy. Reviewing hospital records of patients with dysphagia, our research group reported that while approximately 60 percent of patients were found to have a diagnosis of SCC, the remaining 40% were found to have adenocarcinomas of the lower esophagus or gastric cardia[13]. A case-control study performed on the patients with presumed distal esophageal or gastric cardia cancer in Linzhou found that one third of all these tumors was adenocarcinomas of the gastric cardia[14]. While there is considerable evidence implicating that dietary factors, including certain nutrient deficiencies and consumption of nitrosamine-contaminated food, and drinking water are associated with the development of SCC[15-18], it is not clear whether adenocarcinomas of the gastric cardia share the same risk factors in this high-incidence area in China.


It is generally difficult to distinguish where cardia adenocarcinomas originate, as most tumors present in advanced stage at diagnosis, often involving both esophagus and stomach. Imprecise clinical and pathological definitions of adenocarcinomas of the lower esophagus, EGJ or gastric cardia may be the reason underlying inconsistencies between different studies. An adenocarcinoma is considered to be of cardia origin when the epicenter of the tumor is at the esophagogastric junction, or within 2 cm distally[19]. Strict clinicopathologic criteria have been used also to define primary esophageal adenocarcinomas[20]. A new classification for adenocarcinomas of the esophagogastric junction was proposed at a recent conference of the International Gastric Cancer Association (IGCA) and the International Society for Diseases of the Esophagus (ISDE). Adenocarcinomas of the cardia has been defined as tumors that have their centres within 5 cm of the anatomic esophagogastric junction. Three distinct tumor entities (Type I, II and III) have been proposed[21].

Barrett's esophagus

Barrett's esophagus is the condition in which columnar epithelium replaces the squamous epithelium that normally lines the distal esophagus[22]. The endoscopic appearance is characteristic, with a salmon-pink color and velvety texture. This upward extension may be circumferential, or limited to finger-like projections, or even islands of columnar epithelium that only involve part of the distal esophageal wall[23]. In healthy individuals, the squamo-columnar junction (SCJ) does not always correspond with the anatomic EGJ. The juxtaposition of pale squamous epithelium and reddish columnar epithelium forms a visible line called the Z line, or the SCJ. The EGJ is the most proximate part of gastric folds. The Z line and gastroesophageal junction often coincide. When the Z line is located above the EGJ, there is a columnarly lined segment of esophagus. Barrett's esophagus is diagnosed endoscopically if columnar mucosa extending greater than 3 cm above the EGJ, or by histologic finding of intestinal metaplasia (specialized mucosa) existing at any level of the tubular esophagus[22].

The pathogenesis of Barrett's esophagus is still unclear. Most Barrett's esophagus develops from approximately 10% of persons who have chronic gastroesophageal reflux[24]. In addition to gastroesophageal reflux diseases (GERD), Barrett's esophagus is associated with several other esophageal disorders, such as hiatal hernia[25], and occasionally familial groupings are reported[26-28].

The significance of Barrett's esophagus is its association with the development of esophageal malignancy[29,30]. Patients with Barrett's esophagus have (by conservative estimates) a 30- to 40-fold higher risk of developing esophageal adenocarcinoma than those without[23]. Since the diagnostic criteria for Barrett's esophagus now include the histological finding of intestinal metaplasia, a columnar-lined esophagus less than 3 cm in length is now recognized as short-segment Barrett's esophagus (SSBE), in contrast to the traditional long-segment Barrett's esophagus (LSBE)[31]. The risk of malignancy in SSBE still needs to be determined[32].

In China, Barrett's esophagus used to be regarded as a rare condition, and consequently has not been studied in detail. However, based on an endoscopic survey performed by our research group in the high-risk population in Linzhou, Barrett's esophagus was detected with a frequency of 0.7% (3/402); not as rare as it was considered previously[33]. It has been identified that there is an apparent change of Z line upgrowth among symptom free subjects in the high-incidence area for esophageal cancer in Henan Province. Z line upgrowth is related with epithelial cell hyperproliferation both in gastric cardia and lower segment of esophagus. These results suggest that Z line upgrowth may be one of the characteristic changes, or precancerous lesions related with EGJ carcinogenesis in the high-risk population for GCA in Henan[11]. Further characterizing Barrett's Esophagus, Z line upgrowth, and esophageal and gastric reflux esophagitis in this population may provide new insights into understanding of cardia carcinogenesis[34].

Intestinal metaplasia

Since the diagnostic criteria for Barrett's esophagus based on endoscopy are arbitrary, recent definitions of Barrett's esophagus have included the histologic finding of intestinal metaplasia, regardless of the length of the columnar-lined esophagus[35]. Histologically, three types of columnar epithelium have been observed in Barrett's esophagus: gastric fundic type, junctional type and specialized intestinal metaplasia (IM). Based on the mucin content of the columnar and goblet cells, intestinal metaplasia is histopathologically divided into three types: the complete form (Type I), in which the columnar cells are absorptive and contain neutral mucins, and the two incomplete forms, in which the columnar cells are partly secretory and contain acidic sialomucins (Type II) or sulphomucins (Type III)[36,37]. Type I is the predominant form of intestinal metaplasia found in the stomach, including both benign and malignant conditions. Type III is the least common form in the stomach, but the one most strongly associated with gastric cancer[38]. The incomplete form of intestinal metaplasia also termed specialized columnar epithelium (SCE), is the histological mark of Barrett's esophagus[39].

IM is also associated with GERD, and the frequency of IM is increased with the extention of columnar lining in the esophagus[40]. However, gastritis rather than GERD seems to be a risk factor of cardiac intestinal metaplasia[41]. While complete intestinal metaplasia is a manifestation of multifocal atrophic gastritis, the incomplete form may result from carditis and GERD[42].

It has been hypothesized that Barrett's adenocarcinoma follows the metaplasia-dysplasia-adenocarcinoma sequence (MCS)[43]. Whether intestinal metaplasia is a premalignant lesion for adenocarcinoma of the gastric cardia is still not clear[44]. Several studies showed that dysplasia was infrequently observed in EGJ or gastric cardia with intestinal metaplasia[42,44,45]. These suggest that intestinal metaplasia at the EGJ or gastric cardia is not a high-risk precursor lesion for adenocarcinoma. However, progression from intestinal metaplasia at the EGJ or gastric cardia to dysplasia still requires further characterization[46].

Examination of the adjacent gastric cardia cancer tissue by our research group showed that IM was frequently observed in as high as 20% of the specimens[47]. In contrast, only 0.7% symptom-free subjects in Linzhou were identified with IM in gastric cardia biopsies[33]. Goblet cell was invariably identified on HE stained specimen. Half of the IM lesion was found to have dysplasia. These suggest that IM may be a precursor of gastric cardia adenocarcinoma in Henan, which is not consistent with that in Western countries. The reason is not clear. Standard histologic evaluation fails to reliably differentiate between IM in the esophagus and IM in native cardiac mucosa. Further characterization for subtypes of IM with biohistochemistry and immunohistochemistry will provide important evidence for elucidating the significance of IM in gastric cardia carcinogenesis.

Chronic carditis: H. pylori infection or gastroesophageal reflux disease

IM in the distal stomach is usually a consequence of chronic inflammation, mainly caused by H. pylori infection[48], while the intestinal metaplasia of Barrett's esophagus has been demonstrated to be associated with GERD[49]. Furthermore, recent studies suggested that gastric infection with H. pylori might protect the esophagus from developing of reflux esophagitis and Barrett's esophagus[50-54]. It is reasonable to hypothesize that intestinal metaplasia at the gastric cardia may develop as a consequence of chronic inflammation due to either GERD or infection. Several recent studies have focused on the relative contribution of H. pylori infection and GERD to gastric carditis, however, results have been inconsistent, to date[55-58]. One possible reason may be related to the use of different histopathologic criteria for identification of the gastric cardia. A study of 33 consecutive autopsies in children showed that the length of cardiac epithelium ranged from 1 to 4 mm, with a mean extent of 1.8 mm[59]. Ormsby expanded the study to 223 adult autopsies, finding that the mean extent of cardiac epithelium in patients aged < 18, 19-50, and > 50 years was 1.7, 2.6, and 3.3 mm, respectively[60]. Such a narrow range makes accurate sampling extremely difficult. Therefore, biopsies from the gastric cardia may have two origins: esophagus or stomach.


The pathogenesis of carcinoma has been demonstrated to be a progressive, multi-step process, manifested as an uncontrolled cell cycle and abnormal proliferation. The molecular basis of human cancer has been investigated widely in the recent two decades, and has implicated deregulation of tumor suppressor genes, activation of oncogenes, and aberrant expression of growth factors. Different genetic alterations have been observed between the two different histologic sub-types of esophageal cancer. Meanwhile, molecular evidence is also accumulating to support the hypothesis that adenocarcinomas of the gastric cardia are distinct from adenocarcinomas of the esophagus and stomach.

Loss of heterozygosity (LOH)

LOH has been demonstrated to play an important role in tumorigenesis, and to be frequently associated with the loss of tumor suppressor gene function. LOH was initially observed at several tumor suppressor gene loci (17p, 13q, 5q, 18q and 9p for p53, Rb, APC, MSH2, DCC and p16, E-cadherin, 19p, respectively) in human esophageal and gastric cancer[61-67]. At present, LOH has been used to localize putative tumor suppressor genes. LOH has also been reported at 1p, 3p, 4q, 9q, 11p and 17q in esophageal adenocarcinomas[68,69]. Allelic loss of the tumor suppressor gene p73 on 1p is frequently observed in neuroblastoma[70,71], and hMLH-1, a mismatch repair gene associated with hereditary non-polyposis colorectal cancer, is located on 3q21[72]. The tylosis esophageal cancer (TOC) gene, initially reported in families with autosomal dominant tylosis families who developed esophageal cancer, has been located on chromosome 17q25. Allelic loss at this region has been implicated in both sporadic SCC and Barrett's adenocarcinoma[73]. BCRA1, associated with susceptibility to breast and ovarian cancer, is located on 17q[74]. Using comparative genomic hybridization (CGH), deletion of a specific region at 14q31-32.1 occurred significantly more frequently in Barrett's adenocarcinomas in the distal esophagus than in gastric cardia cancers, suggesting genetic divergence in this group of closely related cancers[75]. Allelotype analysis performed on 38 gastric cardia adenocarcinomas even differentiated this allelic imbalance between the intestinal-type and diffuse-type adenocarcinomas, and a higher frequency of allelic imbalance on chromosome 16q was detected in the diffuse-type adenocarcinomas[76].

Dysfunction of tumor suppressor genes

Tumor suppressor gene p53 P53 is located on chromosome 17p13, encoding a phosphoprotein with a molecular weight of 53 kd. Abnormalities in p53 gene function cause uncontrolled cell cycles and abnormal cell proliferation. P53 mutations are the most frequent genetic alterations found in human cancers[77]. Over 90 percent of p53 mutations are observed in exons 5-8, which is the highly conserved region for DNA binding. Comparison of p53 mutations in premalignant (basal cell hypertrophy, BCH; dysplasia, DYS; carcinoma in situ, CIS) esophageal tissues matched with corresponding invasive SCC tumor tissues, showed similar p53 mutations in DYS, CIS and tumors[78]. Similar studies with Barrett's adenocarcinoma showed that p53 mutations in Barrett's epithelia (metaplasia, non-dysplastic) did not necessarily correspond to the matched adenocarcinoma[20]. The high coincident alterations for P53 in SCC and GCA from the same patient indicate the possibility of similar molecular mechanisms, which provides important molecular basis and etiological clue for similar geographic distribution and risk factors in SCC and GCA[79,80]. These results suggest that some p53 mutations may have a selective tumorigenic advantage during tumor progression. And some findings suggest p53, bcl-2 and caspase-3 may play an important role in the induction of apoptosis in AGS cells[81]. In the course of the formation of gastric carcinoma, proliferation of gastric mucosa can be greatly increased by H. pylori infection, which can strengthen the expression of mutated p53 gene[82]. Less aggressive mutations may increase the genetic instability of Barrett's mucosa, promoting abnormal cellular proliferation, but as they are incapable of transformation independently, additional molecular or epigenetic events are required for tumorigenesis.

About 90 percent of p53 mutations are located within the DNA binding domain (exons 5 to 8). They may occur either at the binding surface or at the hydrophobic core, disrupting the structure for DNA binding. P53 mutations do not distribute in a random manner through the whole encoding region. Several "hot spot" mutations have been located such as codon 175, 176, 245, 248, 249, 273 and 282 in all the human cancers[83], implying that there may be a general pathway for the pathogenesis of tumors with a high percentage of p53 mutations. However, mutation sites also appear to be organ specific and cell-dependent. In esophageal adenocarcinomas, p53 mutations occur most frequently at codon 175 (9%), 248 (16%) and 273 (16%), which are also hot spot mutations for all human cancers recorded, while mutations at codon 248 and 273 are much less frequently observed, even though the mutation at codon 175 accounts for 8% in SCC. Relatively high frequencies of p53 mutations at codons 193, 194, 195 and 270 are unique in comparison to other human cancers[77].

P53 mutations may result from endogenous processes or exogenous carcinogens[84], and the spectrum of mutations may be indicative of specific carcinogenic mechanisms. Mutation profiles of p53 also help to identify the DNA damage arising from environmental carcinogens. Approximately 31% of p53 mutations occur at the A:T base pairs in the SCC, which are usually caused by exogenous carcinogenic compounds. But in esophageal adenocarcinoma, p53 mutations have a very high frequency of transition at the CpG dinucleotides. This alteration is thought to result from spontaneous deamination of 5-methylcytosine, suggesting a defective DNA mismatch repair[77,85]. Differences in p53 mutation spectra between SCC and esophageal adenocarcinoma are consistent with the results of epidemiological studies, suggesting that SCC and esophageal adenocarcinoma have different etiology.

Adenocarcinomas of gastric cardia share similar epidemiological and histological features to esophageal adenocarcinomas in North America and some European countries. Gleeson et al[86] compared the p53 abnormalities in adenocarcinoma of the distal esophagus and gastric cardia, and reported that p53 mutations were detected in 70% and 63% of adenocarcinoma of esophagus and gastric cardia, respectively. 85% of the p53 mutations in esophageal adenocarcinoma occurred as G:C→A:T transitions, with 69% at the CpG dinucleotides. Similar p53 mutations were observed in adenocarcinoma of the gastric cardia, in which 82% were base transitions with 55% occurring at the CpG dinucleotides. One study from Linzhou based on the p53 gene mutation analysis identified 6 mutations among 14 adenocarcinomas of the gastric cardia, 3 of which were G to T transversions, a mutation that is rarely observed in Barrett's adenocarcinoma[87]. Further investigation and comparison of mutation analysis of p53 gene between SCC and adenocarcinoma of the gastric cardia in this population are needed so to provide more insights into the etiology of both SCC and adenocarcinomas of esophagus and the gastric cardia.

p53 gene family Recently, discovery of p53 homologues such as p73 and p63 suggests a more complex pathway. p73 and p63, similar to p53, may result in transactivation, DNA binding and oligomerization domains[88], capable of activating the transcription of p53-responsive genes and inducing apoptosis[89-91]. p73 is located on chromosome 1p36, a region that is frequently deleted in neuroblastoma[73,74], but unlike p53, p73 mutations have been detected infrequently in other types of tumor, including esophageal and gastric carcinoma[92-100]. Silencing of p73 gene due to hypermethylation at its promoter region was observed in a subset of lymphoblastic leukaemia and Burkett's lymphoma[101,102], but increased level of mRNA was more commonly observed in other tumors[95,103-105]. p73 is characterized by loss of imprinting (LOI), resulting in monoallelic expression in normal tissues. It has been observed that p73 is overexpressed in several tumors, which is thought to be due to the switching from monoallellic to biallelic expression[93,95]. Meanwhile, p73 isoforms, caused by alternative splicing, have been observed in rare types of brain tumors, suggesting tissue-specificity in the regulation of p73 gene transcription[106]. However, the precise function of p73 isoforms in tumor development is still unclear. Specific mutations of p73 or p63 causing amino acid substitutions are not identified. Neither p53, p73 nor p63 is related to prognosis. p73 and p63 have rarely been found to be mutated in gastric carcinomas, but both proteins are expressed in only a subset of tumors. The status of these p53 homologues is discordant among all patients with multiple simultaneous gastric carcinomas. The increased expression of p63 (TAp63 and black triangleNp63) in less well-differentiated gastric carcinomas may indicate that p63 can act to promote neoplastic growth in the gastric epithelium[107]. In 15 SCC samples from Henan, no p73 mutations were found in exons 4-7, but a high frequency of LOI and LOH was observed in these samples. The SCC samples with p53 defects were significantly correlated with those, which had elevated expression of p73. These results suggest that increased expression of p73, including that by LOI, could be a partial compensatory mechanism for defective p53[100].

The p63 gene also encodes multiple isoforms through alternative splicing with different abilities to transactivate p53-responsive genes. However, p63 is more closely related to p73 than to p53, and p63 mutations have been rarely observed in human tumors[108,109]. The predominant isoform of p63, lacking in an acidic N-terminus corresponding to the transactivation domain of p53, has been detected in many kinds of epithelial tissue. This truncated protein may act as a dominant-negative agents toward transactivation by p53[110]. Up to date, p63 has not been studied in esophageal adenocarcinoma or adenocarcinomas of the cardia.

Rb gene One study compared LOH with the expression of Rb gene in SCC, finding that 90% of the tumor samples containing LOH showed low or no Rb expression, while only 20% of those without LOH had altered expression of Rb, suggesting LOH is the principal molecular alteration of Rb in SCC[111]. Recent studies of SCC cell lines demonstrated that the hypophosphorylated Rb protein was also associated with G2 arrest[112]. Besides inhibition of the cell cycle progression, Rb protein appears to have other distinct mechanisms to suppress cellular proliferation[113]. In the gastric carcinogenesis, H pylori might cause severe imbalance of proliferation and apoptosis in the precancerous lesions (IMIII and DysIII) first, leading to p53-Rb tumor-suppressor system mutation and telomerase reactivation, and finally causing gastric cancer[114]. Wang et al[115] suggested the alteration of Rb protein might play a role in the early stages of gastric cardia carcinogenesis.

p16INK4a, p15INK4b and p14ARF LOH of p16INK4a has been detected with high frequencies in both SCC (65%) and esophageal adenocarcinoma (69%)[116]. Several studies have demonstrated that hypermethylation of the promoter region of p16INK4a is the main mechanism causing gene silencing rather than point mutation, which rarely occurrs in esophageal carcinomas[116-119]. Distinct from p16INK4a, p15INK4b, which inhibits the cell growth in response to extracellular stimuli such as TGF-β[120], is more frequently deleted, at a frequency of 40%[118]. Though p16INK4a regulates cell cycle through inhibiting the phosphorylation of Rb protein, p14ARF is closely associated with p53 by attenuating mdm2-mediated degradation of p53[121,122]. Similar to p15INK4b, p14ARF is also deleted frequently in SCC, losing its function to protect p53 from ubiqitin-dependent degradation[123].

Abnormalities of oncogenes Point mutation, amplification, rearrangement and overexpression are the most frequent mechanisms for oncogene activation. Amplification of cyclinD1, HER-2/neu(c-erbB2), c-myc, c-ras, Int-2/hst-1 and c-erbB (EGFR) has been observed in gastric and esophageal carcinomas[124-130]. The amplification of c-erbB2 was followed by overexpression in the same gastric adenocarcinoma tissue[125,129]. No amplification of c-erbB2 was detected in SCC. Amplification of oncogenes that encode growth factor receptors is more commonly found in adenocarcinomas. Int-2 and hst-1, encoding FGF-3 and FGR-4 respectively, are located at chromosome 11q13 with the oncogene cyclinD1. Coamplification of int-2 and hst-1 was observed at a frequency of 28%-47% in primary esophageal carcinomas and much higher in metastatic tumors, suggesting an association with tumor progression and distal metastasis[131,132]. CyclinD1, a cell cycle protein, facilitates cell cycle progression from G1 to S phase through combining with CDK4. Both the amplification and overexpression of cyclinD1 were detected in esophageal carcinomas[133,134]. Abnormal expression of cyclin E and p27 may be one of the important molecular changes in the early stage of esophageal carcinogenesis, and the high-expression of cyclin E and low-expression of p27 may be one of the mechanisms driving the mild lesion towards carcinogenesis[135]. In contrast to other gastrointestinal tumors, the ras oncogene is rarely mutated in human esophageal adenocarcinoma[127]. However, overexpression of ras and ras-regulated genes (osteopontin, cathepsin L) has been reported in 58% of primary esophageal adenocarcinomas[136].


Though adenocarcinomas of the lower esophagus and gastric cardia share similar epidemiological characteristics, new clinicopathologic classifications have established criteria to differentiate these two entities. Taniere[137] compared molecular markers in esophageal adenocarcinomas with those in adenocarcinomas of the gastric cardia. The male to female ratio and p53 mutation frequency were higher in esophageal adenocarcinomas, while mdm2 amplification was more frequent in the adenocarcinomas of the gastric cardia. Patterns of cytokeratin immunostaining were also different between these two tumors. Flejou[138] performed a study to compare p53 protein expression immunohistochemically between esophageal and gastric carcinomas, and reported a higher prevalence of p53 protein overexpression was found in esophageal and cardiac adenocarcinomas compared with gastric antral adenocarcinoma. This was confirmed by an additional study, which reported p53 mutation rates in adenocarcinomas of distal stomach were significantly lower than those in adenocarcinomas of esophagus and gastric cardia[139]. These results suggest that adenocarcinoma of the gastric cardia may be a distinct entity from adenocarcinoma of the distal stomach.

Comparison between gastric cardia adenocarcinoma and esophageal squamous cell carcinoma, with special reference to Linzhou

Because of the highly concurrent incidence of gastric cardia adenocarcinoma and esophageal squamous cell carcinoma in Linzhou[140], it is highly desirable to characterize the molecular differences between these tumors of different histological types to explore the possible clues related with etiological risk factors. However, useful information concerning this topic is very limited. In Linzhou, it is not uncommon clinically to identify patients with both gastric cardia adenocarcinoma and esophageal squamous cell carcinoma[141], which is the most common pattern of multiple primary malignant neoplasm (MPN) with an incidence of 0.4%-2.5%[142]. Recent studies from Wang's laboratory showed that there was a highly consistent positive immunostaining rate for p53 in SCC and GCA from the same patient (60%, 12/25 vs 40%, 10/25)[79] similar results were observed for PCNA. p53 mutation analysis in patients with either SCC or GCA from Linzhou indicated that G:C to A:T transition was the most frequent mutation pattern both in SCC and GCA. The consistency of P53 gene mutation was as high as 64%[143]. G to A mutation pattern may be resulted from DNA methylation induced by nitrosamine[141]. These results are of important value in explaining the similar geographic distribution of SCC and GCA in this area. Protein file analysis also showed similar expression pattern in SCC and GCA, such as PTEN[144], c-erbB-2 and c-myc[145], MUC1[146], CYP1A1 and 2E1[147], MUC3[148], mEH[149], GSTM1, GSTT1 and GSTP[150], EGFR[151], etc from the samples in Linzhou.


In summary, the incidence of adenocarcinomas arising from the distal esophagus, EGJ and gastric cardia is increasing at a dramatic rate in North America and Europe. It is suggested that adenocarcinomas of the esophagus develop in a metaplasia- dysplasia-carcinoma sequence. Whether adenocarcinomas of the gastric cardia follow the same pattern needs further study. Although both esophageal squamous cell carcinomas and adenocarcinomas of the gastric cardia have a high incidence in the same high-risk population in Linzhou, little information is available on the molecular and etiological differences between these two tumor types. Metaplasia is a frequent finding in the gastric cardia, but its significance in the development of adenocarcinoma of the gastric cardia is not clear. H. pylori infection, a main factor causing atrophy of the mucosa of distal stomach, also leads to chronic inflammation of the gastric cardia. Though H. pylori has been classified as a Type I carcinogen, the role it plays in gastric cardia carcinogenesis remains unclear. To study adenocarcinoma of the gastric cardia in China, researchers are beginning to evaluate epidemiological, histopathologic and molecular characteristics of the tumor.


We acknowledge the help given by graduate students in Laboratory for Cancer Research, College of Medicine, Zhengzhou University (Drs. Dao-Cun Wang, Ning-Bo Wang, Hui-Xing Yi, Xin-Wei He, She-Gan Gao, Xin-Na Yi, Zhi-Wei Chang, Dong-Ling Xie, Ran Wang, Ya-Nan Jiang, Xiao-Dong L, Xiao-Li Liu) in preparation of the manuscript.


Edited by Zhu LH

1.  Hermanek P, Sobin LH.  TNM classification of malignant tumors. International Union Against Cancer (UICC). 4th editor. 2nd revision. Berlin: Springer 1992; 455-460.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Beahrs OH, Henson DE, Hutter RVP, Kennedy BJ, editors .  American Joint Committee on Cancer: Manual for Staging of Cancer. 4th editor. Philadelphia, Pennsylvania: JB Lippincott 1992; 175-200.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Powell J, McConkey CC. Increasing incidence of adenocarcinoma of the gastric cardia and adjacent sites. Br J Cancer. 1990;62:440-443.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 264]  [Cited by in F6Publishing: 292]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
4.  Blot WJ, Devesa SS, Kneller RW, Fraumeni JF. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA. 1991;265:1287-1289.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1287]  [Cited by in F6Publishing: 1285]  [Article Influence: 40.2]  [Reference Citation Analysis (0)]
5.  Blot WJ, Devesa SS, Fraumeni JF. Continuing climb in rates of esophageal adenocarcinoma: an update. JAMA. 1993;270:1320.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 228]  [Cited by in F6Publishing: 229]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
6.  Pera M, Cameron AJ, Trastek VF, Carpenter HA, Zinsmeister AR. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology. 1993;104:510-513.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Spechler SJ, Robbins AH, Rubins HB, Vincent ME, Heeren T, Doos WG, Colton T, Schimmel EM. Adenocarcinoma and Barrett's esophagus. An overrated risk. Gastroenterology. 1984;87:927-933.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Cameron AJ, Ott BJ, Payne WS. The incidence of adenocarcinoma in columnar-lined (Barrett's) esophagus. N Engl J Med. 1985;313:857-859.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 541]  [Cited by in F6Publishing: 540]  [Article Influence: 14.2]  [Reference Citation Analysis (0)]
9.  Wang HH, Antonioli DA, Goldman H. Comparative features of esophageal and gastric adenocarcinomas: recent changes in type and frequency. Hum Pathol. 1986;17:482-487.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 126]  [Cited by in F6Publishing: 135]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
10.  Vaughan TL, Davis S, Kristal A, Thomas DB. Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev. 1995;4:85-92.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Zhang ZF, Kurtz RC, Sun M, Karpeh M, Yu GP, Gargon N, Fein JS, Georgopoulos SK, Harlap S. Adenocarcinomas of the esophagus and gastric cardia: medical conditions, tobacco, alcohol, and socioeconomic factors. Cancer Epidemiol Biomarkers Prev. 1996;5:761-768.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Gammon MD, Schoenberg JB, Ahsan H, Risch HA, Vaughan TL, Chow WH, Rotterdam H, West AB, Dubrow R, Stanford JL. Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer Inst. 1997;89:1277-1284.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 403]  [Cited by in F6Publishing: 433]  [Article Influence: 16.7]  [Reference Citation Analysis (0)]
13.  Wang LD, Gao WJ, Yang WC, Li XF, Li J, Zou JX, Wang DC, Guo RX. Preliminary analysis of the statistics on 3, 933 cases with esophageal cancer and gastric cardia cancer from the subjects in People's Hospital of Linzhou in 9 years. Henan Yike Daxue Xuebao. 1997;32:9-11.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Li JY, Ershow AG, Chen ZJ, Wacholder S, Li GY, Guo W, Li B, Blot WJ. A case-control study of cancer of the esophagus and gastric cardia in Linxian. Int J Cancer. 1989;43:755-761.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 132]  [Cited by in F6Publishing: 136]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
15.  Yang CS. Research on esophageal cancer in China: a review. Cancer Res. 1980;40:2633-2644.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Lu SH, Chui SX, Yang WX, Hu XN, Guo LP, Li FM. Relevance of N-nitrosamines to oesophageal cancer in China. IARC Sci Publ. 1991;105:11-17.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Yu Y, Taylor PR, Li JY, Dawsey SM, Wang GQ, Guo WD, Wang W, Liu BQ, Blot WJ, Shen Q. Retrospective cohort study of risk-factors for esophageal cancer in Linxian, People's Republic of China. Cancer Causes Control. 1993;4:195-202.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Guo W, Blot WJ, Li JY, Taylor PR, Liu BQ, Wang W, Wu YP, Zheng W, Dawsey SM, Li B. A nested case-control study of oesophageal and stomach cancers in the Linxian nutrition intervention trial. Int J Epidemiol. 1994;23:444-450.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 86]  [Cited by in F6Publishing: 93]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
19.  Wijnhoven BP, Siersema PD, Hop WC, van Dekken H, Tilanus HW. Adenocarcinomas of the distal oesophagus and gastric cardia are one clinical entity. Rotterdam Oesophageal Tumour Study Group. Br J Surg. 1999;86:529-535.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 134]  [Cited by in F6Publishing: 138]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
20.  Casson AG, Mukhopadhyay T, Cleary KR, Ro JY, Levin B, Roth JA. p53 gene mutations in Barrett's epithelium and esophageal cancer. Cancer Res. 1991;51:4495-4499.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg. 1998;85:1457-1459.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 876]  [Cited by in F6Publishing: 924]  [Article Influence: 37.0]  [Reference Citation Analysis (0)]
22.  Spechler SJ. Barrett's esophagus and esophageal adenocarcinoma: pathogenesis, diagnosis, and therapy. Med Clin North Am. 2002;86:1423-145, vii.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 57]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
23.  Spechler SJ, Goyal RK. Barrett's esophagus. N Engl J Med. 1986;315:362-371.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 582]  [Cited by in F6Publishing: 569]  [Article Influence: 15.4]  [Reference Citation Analysis (0)]
24.  Vaughan TL, Kristal AR, Blount PL, Levine DS, Galipeau PC, Prevo LJ, Sanchez CA, Rabinovitch PS, Reid BJ. Nonsteroidal anti-inflammatory drug use, body mass index, and anthropometry in relation to genetic and flow cytometric abnormalities in Barrett's esophagus. Cancer Epidemiol Biomarkers Prev. 2002;11:745-752.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Spechler SJ. Clinical practice. Barrett's Esophagus. N Engl J Med. 2002;346:836-842.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 432]  [Cited by in F6Publishing: 459]  [Article Influence: 21.9]  [Reference Citation Analysis (0)]
26.  Everhart CW, Holtzapple PG, Humphries TJ. Barrett's esophagus: inherited epithelium or inherited reflux. J Clin Gastroenterol. 1983;5:357-358.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 16]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
27.  Crabb DW, Berk MA, Hall TR, Conneally PM, Biegel AA, Lehman GA. Familial gastroesophageal reflux and development of Barrett's esophagus. Ann Intern Med. 1985;103:52-54.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 77]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
28.  Smith RR, Hamilton SR, Boitnott JK, Rogers EL. The spectrum of carcinoma arising in Barrett's esophagus. A clinicopathologic study of 26 patients. Am J Surg Pathol. 1984;8:563-573.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 139]  [Cited by in F6Publishing: 134]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
29.  Bonelli L. Barrett's esophagus: results of a multicentric survey. G.O.S.P.E. (Gruppo Operativo per lo Studio delle Precancerosi Esofagee. Endoscopy. 1993;25:652-654.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 38]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
30.  Reid BJ, Sanchez CA, Blount PL, Levine DS. Barrett's esophagus: cell cycle abnormalities in advancing stages of neoplastic progression. Gastroenterology. 1993;105:119-129.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Weston AP, Krmpotich P, Makdisi WF, Cherian R, Dixon A, McGregor DH, Banerjee SK. Short segment Barrett's esophagus: clinical and histological features, associated endoscopic findings, and association with gastric intestinal metaplasia. Am J Gastroenterol. 1996;91:981-986.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Hamilton SR, Smith RR, Cameron JL. Prevalence and characteristics of Barrett esophagus in patients with adenocarcinoma of the esophagus or esophagogastric junction. Hum Pathol. 1988;19:942-948.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 195]  [Cited by in F6Publishing: 197]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
33.  Wang LD, Feng CW, Zhou Q. Analysis of the screening result of esophageal disease in high risk urban and rural areas of esophageal carcinoma. Henan Yike Daxue Xuebao. 1997;32:6-8.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Wang LD, Zheng S, Fan ZM, Liu B, Feng CW, Sun C, Gao SG, Zhang YR, Guo HQ, Li JL. Changes of Z-line at the gastroesophageal junction in symptom-free subjects from high-incidence area for esophageal cancer in Henan. Zhengzhou Daxue Xuebao Yixueban. 2002;37:733-736.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Gottfried MR, McClave SA, Boyce HW. Incomplete intestinal metaplasia in the diagnosis of columnar lined esophagus (Barrett's esophagus). Am J Clin Pathol. 1989;92:741-746.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Jass JR. Role of intestinal metaplasia in the histogenesis of gastric carcinoma. J Clin Pathol. 1980;33:801-810.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 143]  [Cited by in F6Publishing: 159]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
37.  Filipe MI, Potet F, Bogomoletz WV, Dawson PA, Fabiani B, Chauveinc P, Fenzy A, Gazzard B, Goldfain D, Zeegen R. Incomplete sulphomucin-secreting intestinal metaplasia for gastric cancer. Preliminary data from a prospective study from three centres. Gut. 1985;26:1319-1326.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 138]  [Cited by in F6Publishing: 159]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
38.  Spechler SJ. The role of gastric carditis in metaplasia and neoplasia at the gastroesophageal junction. Gastroenterology. 1999;117:218-228.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 131]  [Cited by in F6Publishing: 130]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
39.  Haggitt RC. Barrett's esophagus, dysplasia, and adenocarcinoma. Hum Pathol. 1994;25:982-993.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 457]  [Cited by in F6Publishing: 478]  [Article Influence: 16.5]  [Reference Citation Analysis (0)]
40.  Gulizia JM, Wang H, Antonioli D, Spechler SJ, Zeroogian J, Goyal R, Shahsafaei A, Chen YY, Odze RD. Proliferative characteristics of intestinalized mucosa in the distal esophagus and gastroesophageal junction (short-segment Barrett's esophagus): a case control study. Hum Pathol. 1999;30:412-418.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 30]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
41.  El-Serag HB, Sonnenberg A, Jamal MM, Kunkel D, Crooks L, Feddersen RM. Characteristics of intestinal metaplasia in the gastric cardia. Am J Gastroenterol. 1999;94:622-627.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 47]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
42.  Voutilainen M, Färkkilä M, Juhola M, Mecklin JP, Sipponen P. Complete and incomplete intestinal metaplasia at the oesophagogastric junction: prevalences and associations with endoscopic erosive oesophagitis and gastritis. Gut. 1999;45:644-648.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 44]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
43.  Prach AT, MacDonald TA, Hopwood DA, Johnston DA. Increasing incidence of Barrett's oesophagus: education, enthusiasm, or epidemiology. Lancet. 1997;350:933.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 132]  [Cited by in F6Publishing: 140]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
44.  Morales TG, Bhattacharyya A, Johnson C, Sampliner RE. Is Barrett's esophagus associated with intestinal metaplasia of the gastric cardia. Am J Gastroenterol. 1997;92:1818-1822.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Morales TG, Sampliner RE, Bhattacharyya A. Intestinal metaplasia of the gastric cardia. Am J Gastroenterol. 1997;92:414-418.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  van Sandick JW, van Lanschot JB, van Felius L, Haringsma J, Tytgat GN, Dekker W, Drillenburg P, Offerhaus GJ, ten Kate FJ. Intestinal metaplasia of the esophagus or esophagogastric junction: evidence of distinct clinical, pathologic, and histochemical staining features. Am J Clin Pathol. 2002;117:117-125.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 21]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
47.  Chen H, Wang LD, Fan ZM, Gao SG, Guo HQ, Guo M. The comparison study of the three histochemical staining methods in gastric cardia intestinal metaplasia staining. Henan Yixue Yanjiu. 2003;12:10-13.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Asaka M, Takeda H, Sugiyama T, Kato M. What role does Helicobacter pylori play in gastric cancer. Gastroenterology. 1997;113:S56-S60.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 114]  [Cited by in F6Publishing: 115]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
49.  Spechler SJ. Barrett's esophagus. Semin Oncol. 1994;21:431-437.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Oberg S, Peters JH, DeMeester TR, Chandrasoma P, Hagen JA, Ireland AP, Ritter MP, Mason RJ, Crookes P, Bremner CG. Inflammation and specialized intestinal metaplasia of cardiac mucosa is a manifestation of gastroesophageal reflux disease. Ann Surg. 1997;226:522-30; discussion 530-2.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 235]  [Cited by in F6Publishing: 267]  [Article Influence: 10.3]  [Reference Citation Analysis (0)]
51.  Csendes A, Smok G, Burdiles P, Sagastume H, Rojas J, Puente G, Quezada F, Korn O. 'Carditis': an objective histological marker for pathologic gastroesophageal reflux disease. Dis Esophagus. 1998;11:101-105.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Goldblum JR, Vicari JJ, Falk GW, Rice TW, Peek RM, Easley K, Richter JE. Inflammation and intestinal metaplasia of the gastric cardia: the role of gastroesophageal reflux and H. pylori infection. Gastroenterology. 1998;114:633-639.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 192]  [Cited by in F6Publishing: 203]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
53.  Chen YY, Antonioli DA, Spechler SJ, Zeroogian JM, Goyal RK, Wang HH. Gastroesophageal reflux disease versus Helicobacter pylori infection as the cause of gastric carditis. Mod Pathol. 1998;11:950-956.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Zhang YR, Gao SS, Liu G, An JY, Li JL, Jiao XY, Wang LD. Comparison of Helicobacter pylori (HP) infection in the cardia and pylori parts of the stomach from symptom-free subjects at high-incidence area for esophageal and gastric cardia cancer in Henan. Zhengzhou Daxue Xuebao Yixuebao. 2002;37:777-779.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Loffeld RJ, van der Hulst RW. Helicobacter pylori and gastro-oesophageal reflux disease: association and clinical implications. To treat or not to treat with anti-H. pylori therapy. Scand J Gastroenterol Suppl. 2002;236:15-18.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 12]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
56.  Labenz J, Blum AL, Bayerdörffer E, Meining A, Stolte M, Börsch G. Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology. 1997;112:1442-1447.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 445]  [Cited by in F6Publishing: 449]  [Article Influence: 17.3]  [Reference Citation Analysis (0)]
57.  Chow WH, Blaser MJ, Blot WJ, Gammon MD, Vaughan TL, Risch HA, Perez-Perez GI, Schoenberg JB, Stanford JL, Rotterdam H. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Res. 1998;58:588-590.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Vicari JJ, Peek RM, Falk GW, Goldblum JR, Easley KA, Schnell J, Perez-Perez GI, Halter SA, Rice TW, Blaser MJ. The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology. 1998;115:50-57.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 242]  [Cited by in F6Publishing: 252]  [Article Influence: 10.1]  [Reference Citation Analysis (0)]
59.  Ormsby AH, Kilgore SP, Goldblum JR, Richter JE, Rice TW, Gramlich TL. The location and frequency of intestinal metaplasia at the esophagogastric junction in 223 consecutive autopsies: implications for patient treatment and preventive strategies in Barrett's esophagus. Mod Pathol. 2000;13:614-620.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 58]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
60.  Ormsby AH, Goldblum JR, Rice TW, Richter JE, Falk GW, Vaezi MF, Gramlich TL. Cytokeratin subsets can reliably distinguish Barrett's esophagus from intestinal metaplasia of the stomach. Hum Pathol. 1999;30:288-294.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 165]  [Cited by in F6Publishing: 175]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
61.  El-Rifai W, Powell SM. Molecular biology of gastric cancer. Semin Radiat Oncol. 2002;12:128-140.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 87]  [Cited by in F6Publishing: 92]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
62.  Zhang QX, Ding Y, Le XP, Du P. Studies on microsatellite instability in p16 gene and expression of hMSH2 mRNA in human gastric cancer tissues. World J Gastroenterol. 2003;9:437-441.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Chae KS, Ryu BK, Lee MG, Byun DS, Chi SG. Expression and mutation analyses of MKK4, a candidate tumour suppressor gene encoded by chromosome 17p, in human gastric adenocarcinoma. Eur J Cancer. 2002;38:2048-2057.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 16]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
64.  van Rees BP, Caspers E, zur Hausen A, van den Brule A, Drillenburg P, Weterman MA, Offerhaus GJ. Different pattern of allelic loss in Epstein-Barr virus-positive gastric cancer with emphasis on the p53 tumor suppressor pathway. Am J Pathol. 2002;161:1207-1213.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 38]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
65.  Chang YT, Wu MS, Chang CJ, Huang PH, Hsu SM, Lin JT. Preferential loss of Fhit expression in signet-ring cell and Krukenberg subtypes of gastric cancer. Lab Invest. 2002;82:1201-1208.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 10]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
66.  Becker KF, Kremmer E, Eulitz M, Schulz S, Mages J, Handschuh G, Wheelock MJ, Cleton-Jansen AM, Höfler H, Becker I. Functional allelic loss detected at the protein level in archival human tumours using allele-specific E-cadherin monoclonal antibodies. J Pathol. 2002;197:567-574.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 22]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
67.  Wang Q, Chen H, Bai J, Wang B, Wang K, Gao H, Wang Z, Wang S, Zhang Q, Fu S. [Analysis of loss of heterozygosity on 19p in primary gastric cancer]. Zhonghua Yixue Yichuanzue Zazhi. 2001;18:459-461.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Hammoud ZT, Kaleem Z, Cooper JD, Sundaresan RS, Patterson GA, Goodfellow PJ. Allelotype analysis of esophageal adenocarcinomas: evidence for the involvement of sequences on the long arm of chromosome 4. Cancer Res. 1996;56:4499-4502.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Dolan K, Garde J, Gosney J, Sissons M, Wright T, Kingsnorth AN, Walker SJ, Sutton R, Meltzer SJ, Field JK. Allelotype analysis of oesophageal adenocarcinoma: loss of heterozygosity occurs at multiple sites. Br J Cancer. 1998;78:950-957.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 63]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
70.  Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell. 1997;90:809-819.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1224]  [Cited by in F6Publishing: 1287]  [Article Influence: 49.5]  [Reference Citation Analysis (0)]
71.  White PS, Maris JM, Beltinger C, Sulman E, Marshall HN, Fujimori M, Kaufman BA, Biegel JA, Allen C, Hilliard C. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3. Proc Natl Acad Sci U S A. 1995;92:5520-5524.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 188]  [Cited by in F6Publishing: 195]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
72.  Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994;263:1625-1629.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1335]  [Cited by in F6Publishing: 1402]  [Article Influence: 48.3]  [Reference Citation Analysis (0)]
73.  Risk JM, Mills HS, Garde J, Dunn JR, Evans KE, Hollstein M, Field JK. The tylosis esophageal cancer (TOC) locus: more than just a familial cancer gene. Dis Esophagus. 1999;12:173-176.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 38]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
74.  Mori T, Aoki T, Matsubara T, Iida F, Du X, Nishihira T, Mori S, Nakamura Y. Frequent loss of heterozygosity in the region including BRCA1 on chromosome 17q in squamous cell carcinomas of the esophagus. Cancer Res. 1994;54:1638-1640.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  van Dekken H, Geelen E, Dinjens WN, Wijnhoven BP, Tilanus HW, Tanke HJ, Rosenberg C. Comparative genomic hybridization of cancer of the gastroesophageal junction: deletion of 14Q31-32.1 discriminates between esophageal (Barrett's) and gastric cardia adenocarcinomas. Cancer Res. 1999;59:748-752.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Gleeson CM, Sloan JM, McGuigan JA, Ritchie AJ, Weber JL, Russell SE. Allelotype analysis of adenocarcinoma of the gastric cardia. Br J Cancer. 1997;76:1455-1465.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 29]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
77.  Hollstein M, Shomer B, Greenblatt M, Soussi T, Hovig E, Montesano R, Harris CC. Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucleic Acids Res. 1996;24:141-146.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 326]  [Cited by in F6Publishing: 358]  [Article Influence: 13.3]  [Reference Citation Analysis (0)]
78.  Shi ST, Yang GY, Wang LD, Xue Z, Feng B, Ding W, Xing EP, Yang CS. Role of p53 gene mutations in human esophageal carcinogenesis: results from immunohistochemical and mutation analyses of carcinomas and nearby non-cancerous lesions. Carcinogenesis. 1999;20:591-597.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 55]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
79.  Chen H, Wang LD, Guo M, Gao SG, Guo HQ, Fan ZM, Li JL. Alterations of p53 and PCNA in cancer and adjacent tissues from concurrent carcinomas of the esophagus and gastric cardia in the same patient in Linzhou, a high incidence area for esophageal cancer in northern China. World J Gastroenterol. 2003;9:16-21.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Feng CW, Wang LD, Jiao LH, Liu B, Zheng S, Xie XJ. Expression of p53, inducible nitric oxide synthase and vascular endothelial growth factor in gastric precancerous and cancerous lesions: correlation with clinical features. BMC Cancer. 2002;2:8.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 28]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
81.  Li HL, Chen DD, Li XH, Zhang HW, Lu YQ, Ye CL, Ren XD. Changes of NF-κB, p53, Bcl-2 and caspase in apoptosis induced by JTE-522 in human gastric adenocarcinoma cell line AGS cells: role of reactive oxygen species. World J Gastroenterol. 2002;8:431-435.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Zhang Z, Yuan Y, Gao H, Dong M, Wang L, Gong YH. Apoptosis, proliferation and p53 gene expression of H. pylori associated gastric epithelial lesions. World J Gastroenterol. 2001;7:779-782.  [PubMed]  [DOI]  [Cited in This Article: ]
83.  Wang LD, Liu B, Zheng S. [Analysis of p53 mutational spectra of esophageal squamous cell carcinomas from Linzhou, comparison with esophageal and other cancers from other areas]. Zhonghua Liuxingbingxue Zazhi. 2003;24:202-205.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855-4878.  [PubMed]  [DOI]  [Cited in This Article: ]
85.  Montesano R, Hollstein M, Hainaut P. Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: a review. Int J Cancer. 1996;69:225-235.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 5]  [Reference Citation Analysis (0)]
86.  Gleeson CM, Sloan JM, McManus DT, Maxwell P, Arthur K, McGuigan JA, Ritchie AJ, Russell SE. Comparison of p53 and DNA content abnormalities in adenocarcinoma of the oesophagus and gastric cardia. Br J Cancer. 1998;77:277-286.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 69]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
87.  Liang YY, Estève A, Martel-Planche G, Takahashi S, Lu SH, Montesano R, Hollstein M. p53 mutations in esophageal tumors from high-incidence areas of China. Int J Cancer. 1995;61:611-614.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 22]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
88.  Arrowsmith CH. Structure and function in the p53 family. Cell Death Differ. 1999;6:1169-1173.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 84]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
89.  Kaelin WG. The emerging p53 gene family. J Natl Cancer Inst. 1999;91:594-598.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 108]  [Cited by in F6Publishing: 109]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
90.  Sheikh MS, Fornace AJ. Role of p53 family members in apoptosis. J Cell Physiol. 2000;182:171-181.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
91.  Bénard J, Douc-Rasy S, Ahomadegbe JC. TP53 family members and human cancers. Hum Mutat. 2003;21:182-191.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 160]  [Cited by in F6Publishing: 171]  [Article Influence: 8.6]  [Reference Citation Analysis (0)]
92.  Takahashi H, Ichimiya S, Nimura Y, Watanabe M, Furusato M, Wakui S, Yatani R, Aizawa S, Nakagawara A. Mutation, allelotyping, and transcription analyses of the p73 gene in prostatic carcinoma. Cancer Res. 1998;58:2076-2077.  [PubMed]  [DOI]  [Cited in This Article: ]
93.  Mai M, Yokomizo A, Qian C, Yang P, Tindall DJ, Smith DI, Liu W. Activation of p73 silent allele in lung cancer. Cancer Res. 1998;58:2347-2349.  [PubMed]  [DOI]  [Cited in This Article: ]
94.  Tsao H, Zhang X, Majewski P, Haluska FG. Mutational and expression analysis of the p73 gene in melanoma cell lines. Cancer Res. 1999;59:172-174.  [PubMed]  [DOI]  [Cited in This Article: ]
95.  Chi SG, Chang SG, Lee SJ, Lee CH, Kim JI, Park JH. Elevated and biallelic expression of p73 is associated withprogression of human bladder cancer. Cancer Res. 1999;59:2791-2793.  [PubMed]  [DOI]  [Cited in This Article: ]
96.  Yoshikawa H, Nagashima M, Khan MA, McMenamin MG, Hagiwara K, Harris CC. Mutational analysis of p73 and p53 in human cancer cell lines. Oncogene. 1999;18:3415-3421.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 46]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
97.  Yokozaki H, Shitara Y, Fujimoto J, Hiyama T, Yasui W, Tahara E. Alterations of p73 preferentially occur in gastric adenocarcinomas with foveolar epithelial phenotype. Int J Cancer. 1999;83:192-196.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 4]  [Reference Citation Analysis (0)]
98.  Mihara M, Nimura Y, Ichimiya S, Sakiyama S, Kajikawa S, Adachi W, Amano J, Nakagawara A. Absence of mutation of the p73 gene localized at chromosome 1p36.3 in hepatocellular carcinoma. Br J Cancer. 1999;79:164-167.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 29]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
99.  Nimura Y, Mihara M, Ichimiya S, Sakiyama S, Seki N, Ohira M, Nomura N, Fujimori M, Adachi W, Amano J. p73, a gene related to p53, is not mutated in esophageal carcinomas. Int J Cancer. 1998;78:437-440.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 2]  [Reference Citation Analysis (0)]
100.  Cai YC, Yang GY, Nie Y, Wang LD, Zhao X, Song YL, Seril DN, Liao J, Xing EP, Yang CS. Molecular alterations of p73 in human esophageal squamous cell carcinomas: loss of heterozygosity occurs frequently; loss of imprinting and elevation of p73 expression may be related to defective p53. Carcinogenesis. 2000;21:683-689.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 71]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
101.  Kawano S, Miller CW, Gombart AF, Bartram CR, Matsuo Y, Asou H, Sakashita A, Said J, Tatsumi E, Koeffler HP. Loss of p73 gene expression in leukemias/lymphomas due to hypermethylation. Blood. 1999;94:1113-1120.  [PubMed]  [DOI]  [Cited in This Article: ]
102.  Corn PG, Kuerbitz SJ, van Noesel MM, Esteller M, Compitello N, Baylin SB, Herman JG. Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5' CpG island methylation. Cancer Res. 1999;59:3352-3356.  [PubMed]  [DOI]  [Cited in This Article: ]
103.  Zaika AI, Kovalev S, Marchenko ND, Moll UM. Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. Cancer Res. 1999;59:3257-3263.  [PubMed]  [DOI]  [Cited in This Article: ]
104.  Tokuchi Y, Hashimoto T, Kobayashi Y, Hayashi M, Nishida K, Hayashi S, Imai K, Nakachi K, Ishikawa Y, Nakagawa K. The expression of p73 is increased in lung cancer, independent of p53 gene alteration. Br J Cancer. 1999;80:1623-1629.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 61]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
105.  Yokomizo A, Mai M, Tindall DJ, Cheng L, Bostwick DG, Naito S, Smith DI, Liu W. Overexpression of the wild type p73 gene in human bladder cancer. Oncogene. 1999;18:1629-1633.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 88]  [Cited by in F6Publishing: 97]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
106.  Loiseau H, Arsaut J, Demotes-Mainard J. p73 gene transcripts in human brain tumors: overexpression and altered splicing in ependymomas. Neurosci Lett. 1999;263:173-176.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 26]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
107.  Tannapfel A, Schmelzer S, Benicke M, Klimpfinger M, Kohlhaw K, Mössner J, Engeland K, Wittekind C. Expression of the p53 homologues p63 and p73 in multiple simultaneous gastric cancer. J Pathol. 2001;195:163-170.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 51]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
108.  Hagiwara K, McMenamin MG, Miura K, Harris CC. Mutational analysis of the p63/p73L/p51/p40/CUSP/KET gene in human cancer cell lines using intronic primers. Cancer Res. 1999;59:4165-4169.  [PubMed]  [DOI]  [Cited in This Article: ]
109.  Kato S, Shimada A, Osada M, Ikawa S, Obinata M, Nakagawara A, Kanamaru R, Ishioka C. Effects of p51/p63 missense mutations on transcriptional activities of p53 downstream gene promoters. Cancer Res. 1999;59:5908-5911.  [PubMed]  [DOI]  [Cited in This Article: ]
110.  Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, Andrews NC, Caput D, McKeon F. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell. 1998;2:305-316.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1569]  [Cited by in F6Publishing: 1642]  [Article Influence: 65.7]  [Reference Citation Analysis (0)]
111.  Xing EP, Yang GY, Wang LD, Shi ST, Yang CS. Loss of heterozygosity of the Rb gene correlates with pRb protein expression and associates with p53 alteration in human esophageal cancer. Clin Cancer Res. 1999;5:1231-1240.  [PubMed]  [DOI]  [Cited in This Article: ]
112.  Rigberg DA, Kim FS, Sebastian JL, Kazanjian KK, McFadden DW. Hypophosphorylated retinoblastoma protein is associated with G2 arrest in esophageal squamous cell carcinoma. J Surg Res. 1999;84:101-105.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 10]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
113.  Knudsen KE, Weber E, Arden KC, Cavenee WK, Feramisco JR, Knudsen ES. The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death. Oncogene. 1999;18:5239-5245.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 48]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
114.  Lan J, Xiong YY, Lin YX, Wang BC, Gong LL, Xu HS, Guo GS. Helicobacter pylori infection generated gastric cancer through p53-Rb tumor-suppressor system mutation and telomerase reactivation. World J Gastroenterol. 2003;9:54-58.  [PubMed]  [DOI]  [Cited in This Article: ]
115.  Zhou Y, Gao SS, Li YX, Fan ZM, Zhao X, Qi YJ, Wei JP, Zou JX, Liu G, Jiao LH. Tumor suppressor gene p16 and Rb expression in gastric cardia precancerous lesions from subjects at a high incidence area in northern China. World J Gastroenterol. 2002;8:423-425.  [PubMed]  [DOI]  [Cited in This Article: ]
116.  Muzeau F, Fléjou JF, Thomas G, Hamelin R. Loss of heterozygosity on chromosome 9 and p16 (MTS1, CDKN2) gene mutations in esophageal cancers. Int J Cancer. 1997;72:27-30.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 2]  [Reference Citation Analysis (0)]
117.  Wong DJ, Barrett MT, Stöger R, Emond MJ, Reid BJ. p16INK4a promoter is hypermethylated at a high frequency in esophageal adenocarcinomas. Cancer Res. 1997;57:2619-2622.  [PubMed]  [DOI]  [Cited in This Article: ]
118.  Xing EP, Nie Y, Wang LD, Yang GY, Yang CS. Aberrant methylation of p16INK4a and deletion of p15INK4b are frequent events in human esophageal cancer in Linxian, China. Carcinogenesis. 1999;20:77-84.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 89]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
119.  Tsujimoto H, Hagiwara A, Sugihara H, Hattori T, Yamagishi H. Promoter methylations of p16INK4a and p14ARF genes in early and advanced gastric cancer. Correlations of the modes of their occurrence with histologic type. Pathol Res Pract. 2002;198:785-794.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 15]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
120.  Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994;371:257-261.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1470]  [Cited by in F6Publishing: 1548]  [Article Influence: 53.4]  [Reference Citation Analysis (0)]
121.  Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH. p14ARF links the tumour suppressors RB and p53. Nature. 1998;395:124-125.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 693]  [Cited by in F6Publishing: 727]  [Article Influence: 29.1]  [Reference Citation Analysis (0)]
122.  Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998;17:5001-5014.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 841]  [Cited by in F6Publishing: 886]  [Article Influence: 35.4]  [Reference Citation Analysis (0)]
123.  Xing EP, Nie Y, Song Y, Yang GY, Cai YC, Wang LD, Yang CS. Mechanisms of inactivation of p14ARF, p15INK4b, and p16INK4a genes in human esophageal squamous cell carcinoma. Clin Cancer Res. 1999;5:2704-2713.  [PubMed]  [DOI]  [Cited in This Article: ]
124.  Yokota J, Yamamoto T, Miyajima N, Toyoshima K, Nomura N, Sakamoto H, Yoshida T, Terada M, Sugimura T. Genetic alterations of the c-erbB-2 oncogene occur frequently in tubular adenocarcinoma of the stomach and are often accompanied by amplification of the v-erbA homologue. Oncogene. 1988;2:283-287.  [PubMed]  [DOI]  [Cited in This Article: ]
125.  Park JB, Rhim JS, Park SC, Kimm SW, Kraus MH. Amplification, overexpression, and rearrangement of the erbB-2 protooncogene in primary human stomach carcinomas. Cancer Res. 1989;49:6605-6609.  [PubMed]  [DOI]  [Cited in This Article: ]
126.  Persons DL, Croughan WS, Borelli KA, Cherian R. Interphase cytogenetics of esophageal adenocarcinoma and precursor lesions. Cancer Genet Cytogenet. 1998;106:11-17.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 42]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
127.  Hollstein MC, Smits AM, Galiana C, Yamasaki H, Bos JL, Mandard A, Partensky C, Montesano R. Amplification of epidermal growth factor receptor gene but no evidence of ras mutations in primary human esophageal cancers. Cancer Res. 1988;48:5119-5123.  [PubMed]  [DOI]  [Cited in This Article: ]
128.  Tsuda T, Tahara E, Kajiyama G, Sakamoto H, Terada M, Sugimura T. High incidence of coamplification of hst-1 and int-2 genes in human esophageal carcinomas. Cancer Res. 1989;49:5505-5508.  [PubMed]  [DOI]  [Cited in This Article: ]
129.  Houldsworth J, Cordon-Cardo C, Ladanyi M, Kelsen DP, Chaganti RS. Gene amplification in gastric and esophageal adenocarcinomas. Cancer Res. 1990;50:6417-6422.  [PubMed]  [DOI]  [Cited in This Article: ]
130.  Chen H, Wang LD, Gao SG, Fan ZM, Guo HQ. Alterations of MUC1, C-erbB2 in concurrent cancers of the esophagus and gastric cardia from the same patient in Linzhou, Henan province, a high incidence area for esophageal cancer. Zhengzhou Daxue Xuebao (YiXueBan). 2002;37:758-761.  [PubMed]  [DOI]  [Cited in This Article: ]
131.  Tsuda T, Tahara E, Kajiyama G, Sakamoto H, Terada M, Sugimura T. High incidence of coamplification of hst-1 and int-2 genes in human esophageal carcinomas. Cancer Res. 1989;49:5505-5508.  [PubMed]  [DOI]  [Cited in This Article: ]
132.  Kitagawa Y, Ueda M, Ando N, Shinozawa Y, Shimizu N, Abe O. Significance of int-2/hst-1 coamplification as a prognostic factor in patients with esophageal squamous carcinoma. Cancer Res. 1991;51:1504-1508.  [PubMed]  [DOI]  [Cited in This Article: ]
133.  Jiang W, Kahn SM, Tomita N, Zhang YJ, Lu SH, Weinstein IB. Amplification and expression of the human cyclin D gene in esophageal cancer. Cancer Res. 1992;52:2980-2983.  [PubMed]  [DOI]  [Cited in This Article: ]
134.  Adélaide J, Monges G, Dérdérian C, Seitz JF, Birnbaum D. Oesophageal cancer and amplification of the human cyclin D gene CCND1/PRAD1. Br J Cancer. 1995;71:64-68.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 68]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
135.  Qin YR, Liu Z, Guo HQ, Gao SS, Fan ZM, Li JX. Expression of tumor suppressor gene p27 and cyclinE in esophageal precancerous lesions from the subjects at high-incidence area for esophageal cancer in Henan. Zhengzhou Daxue Xuebao (Yixueban). 2002;37:733-736.  [PubMed]  [DOI]  [Cited in This Article: ]
136.  Casson AG, Wilson SM, McCart JA, O'Malley FP, Ozcelik H, Tsao MS, Chambers AF. ras mutation and expression of the ras-regulated genes osteopontin and cathepsin L in human esophageal cancer. Int J Cancer. 1997;72:739-745.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
137.  Tanière P, Martel-Planche G, Maurici D, Lombard-Bohas C, Scoazec JY, Montesano R, Berger F, Hainaut P. Molecular and clinical differences between adenocarcinomas of the esophagus and of the gastric cardia. Am J Pathol. 2001;158:33-40.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 51]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
138.  Fléjou JF, Muzeau F, Potet F, Lepelletier F, Fékété F, Hénin D. Overexpression of the p53 tumor suppressor gene product in esophageal and gastric carcinomas. Pathol Res Pract. 1994;190:1141-1148.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 23]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
139.  Ireland AP, Shibata DK, Chandrasoma P, Lord RV, Peters JH, DeMeester TR. Clinical significance of p53 mutations in adenocarcinoma of the esophagus and cardia. Ann Surg. 2000;231:179-187.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 55]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
140.  Wang LD, Zheng S. Mechanisms of human esophageal and gastric cardia cancer on the subjects in Henan, the high incidence area for esophageal cancer. Zhengzhou Daxue Xuebao (Yixueban). 2002;37:717-729.  [PubMed]  [DOI]  [Cited in This Article: ]
141.  Chen H, Wang LD, Gao SG, Fan ZM, Guo HQ, Li JL, Guo M. Alterations of MUC1, C-erbB2 in concurrent cancers of the esophagus and gastric cardia from the same patient in Linzhou, Henan province, a high incidence area for esophageal cancer. Zhengzhou Daxue Xuebao (Yixueban). 2002;37:758-760.  [PubMed]  [DOI]  [Cited in This Article: ]
142.  Zhou Q, Wang LD. Biological characteristics of gastric cardia adenocarcinoma. ShiJie Xiaohua Zazhi. 1998;6:636-637.  [PubMed]  [DOI]  [Cited in This Article: ]
143.  Zhou Q, Zheng ZY, Wang LD, Liu B, Qin YR, Wang DC, Chang ZW, Yi HX, Fan ZM, Li JL. p53 protein accumulation and p53 gene mutation in esophageal and gastric cardia cancer from the patients at Linzhou, Henan. Zhengzhou Daxue Xuebao (Yixueban). 2003;38:313-316.  [PubMed]  [DOI]  [Cited in This Article: ]
144.  An JY, Wang LD, He XW, Wang QM, Fan ZM, Gao SS, Guo HQ. Changes of PTEN expression in esophageal squamous cell carcinomas and gastric cardia adenocarcinoma from the patients at high-incidence area for esophageal cancer in Henan. Zhengzhou Daxue Xuebao (Yixueban). 2002;37:750-753.  [PubMed]  [DOI]  [Cited in This Article: ]
145.  Wang LD, Liu B, Guo RF, Bai YM, Sun C, Yi XN, He XW, Xie DL, Fan ZM, Ding ZH. Changes of c-erbB-2 and c-myc expression in esophageal and gastric cardia carcinogenesis from the subjects at high-incidence area for esophageal cancer in Henan, China. Zhengzhou Daxue Xuebao (Yixueban). 2002;37:739-742.  [PubMed]  [DOI]  [Cited in This Article: ]
146.  Zhuang ZH, Wang LD, Gao SS, Fan ZM, Song ZB, QI YJ, LI YJ, LI JX. Expression of MUC1 in esophageal and gastric cardiac carcinoma: a study on the subjects at high-incidence area for esophageal cancer in Henan, China. Zhengzhou Daxue Xuebao (Yixueban). 2002;37:774-777.  [PubMed]  [DOI]  [Cited in This Article: ]
147.  Zhou Q, Zheng ZY, Wang LD, Liu B, Gao SHG, Guo RF, Fan ZM, Guo HQ, Li JL. Prevalence of genetic polymorphisms of CYP1A1 and 2E1 in subjects with gastric cardia adenocarcinoma at Linzhou, Henan. Zhengzhou Daxue Xuebao (Yixueban). 2003;38:317-320.  [PubMed]  [DOI]  [Cited in This Article: ]
148.  Zhou Q, Bai YM, Wang LD, Liu B, Gao SS, Fan ZM, Guo HQ, Wang QM, Qin YJ, Li JL. Alterations of MUC3 in gastric- cardia precancerous and cancerous lesions: A comparative study between the high- and low-risk populations. Zhengzhou Daxue Xuebao (Yixueban). 2003;38:324-326.  [PubMed]  [DOI]  [Cited in This Article: ]
149.  Zhou Q, Zheng ZY, Wang LD, Fan ZM, Guo HQ, Gao SHG, Qin YR, An JY, He XW, Wang QM. Polymorphism of mEH in gastric cardia carcinogenesis from the subjects at Linzhou, Henan. Zhengzhou Daxue Xuebao (Yixueban). 2003;38:321-323.  [PubMed]  [DOI]  [Cited in This Article: ]
150.  Zhou Q, Zheng ZY, Wang LD, Yi XN, Wang DC, Chang ZW, Liu B, Li JL. Prevalence of genetic polymorphisms of GSTM1, GSTT1 and GSTP1 in subjects with gastric cardia adenocarcinoma at Linzhou, Henan. Zhengzhou Daxue Xuebao (Yixueban). 2003;38:327-329.  [PubMed]  [DOI]  [Cited in This Article: ]
151.  Zhou Q, Bai YM, Liu B, He XW, Fan ZM, Li JL, Gao SS, Guo HQ, Wang DC, He XW. Alterations of EGFR in gastric-cardia precancerous and cancerous lesions: A comparative study between the high and low risk populations. Zhengzhou Daxue Xuebao (Yixueban). 2003;38:332-334.  [PubMed]  [DOI]  [Cited in This Article: ]