Activation of c-K-ras mutations in human gastrointestinal tumors

Arber, Nadir; Shapira, Itzhak; Ratan, John; Stern, Baruch; Hibshoosh, Hanina; Moshkowitz, Menhachem; Gammon, Marilie D.; Fabian, Ina; Halpern, Zamir

doi:10.1016/s0016-5085(00)70357-x

Cited by 102 publications

(74 citation statements)

References 38 publications

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“…Our data on K-ras mutations in H. Pylori-CG suggest that the mutation may be mainly involved in the development of gastric cancer. Our data on K-ras mutations in gastric cancers are in contrast to those of Nanus et al, 8 however, who found 1 (3.6%) case of K-ras mutation in a series of 28 gastric cancers and Arber et al, 5 who found 1 (3.1%) case of K-ras mutation in a series of 32 gastric cancers. These authors concluded that the mutation in K-ras is an uncommon event in primary gastric cancers.…”

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confidence: 99%

“…3 Frequency of mutated K-ras varies among the different tumor types. 4,5 Point mutations of the K-ras are found predominantly in adenocarcinomas. The highest incidence is found in adenocarcinomas of the pancreas, in which approximately 90% of the tumors harbor mutated K-ras.…”

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confidence: 99%

“…Several studies have reported a low incidence of K-ras mutations in gastric cancers, although most studies analyzed a relatively small number of cases. 5,8,9 The frequency and clinicopathologic significance of K-ras mutations in gastric cancers remains to be determined. In addition, gastric cancers are often preceded by Helicobacter pylori-associated chronic gastritis (H. pylori-CG) with or without intestinal metaplasia, which is associated with an increased risk for the gastric cancer development.…”

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confidence: 99%

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K‐ras mutation in helicobacter pylori‐associated chronic gastritis in patients with and without gastric cancer

Hiyama

Haruma

Kitadai

et al. 2001

Intl Journal of Cancer

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Mutations of an oncogene, K-ras, are associated with the development and progression of many types of human cancer. To elucidate the significance of K-ras mutations in gastric carcinogenesis, we examined K-ras mutations in gastric cancers and in Helicobacter pylori-associated chronic gastritis (H. pylori-CG), which is associated with an increased risk for the gastric cancer development. Specimens of gastric cancer and H. pylori-CG were obtained from 64 gastric cancer patients with H. pylori-CG, 99 cancer-free H. pylori-CG patients and 30 H. pylori-negative healthy subjects. K-ras mutations were examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), followed by DNA sequencing analysis. K-ras mutations were detected in 4 of 48 (8.3%) gastric cancers, in 10 of 163 (6.1%) H. pylori-CG and none of the 30 H. pylori-negative healthy subjects. In the gastric cancer patients, mutated K-ras was detected in differentiated type cancers but not in any of the undifferentiated type cancers. K-ras mutations in H. pylori-CG were significantly more frequent in gastric cancer patients than in cancer-free patients (10.9% vs. 3.0%, p ‫؍‬ 0.044). In addition, K-ras mutations in H. pylori-CG were significantly more frequent in patients with K-ras mutated gastric cancer than in patients with K-ras unmutated gastric cancer (50.0% vs. 3.7%, p ‫؍‬ 0.037). These data suggest that the genetic mechanism(s) of carcinogenesis differs between the differentiated type and the undifferentiated type of gastric cancer and that K-ras mutations may be involved in the early stages of gastric carcinogenesis of the differentiated type.

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K‐ras mutation in helicobacter pylori‐associated chronic gastritis in patients with and without gastric cancer

Hiyama

Haruma

Kitadai

et al. 2001

Intl Journal of Cancer

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“…By microsatellite analysis they have found low frequencies of deletions at chromosomal arms 5q, the location of the APC gene, and at 18q, where the DCC-, and DPC4/SMAD4 genes are located. The frequency of replication errors, k-ras mutations, and deletions at 17p, the location of the p53 gene, were reported to be similar to the frequency in colorectal carcinomas (Rashid and Hamilton, 1997;Sutter et al, 1996;Arber et al, 2000), while mutational analysis of APC showed infrequent genetic inactivation of this gene in small intestinal carcinomas (Arai et al, 1997).…”

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confidence: 79%

Genetics of adenocarcinomas of the small intestine: frequent deletions at chromosome 18q and mutations of the SMAD4 gene

et al. 2002

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The small intestinal mucosa makes up about 90% of the total surface of the gastrointestinal tract. However, adenocarcinomas arise rarely in this location. To elucidate genetic alterations underlying tumour development in the small intestine we investigated 17 sporadic adenocarcinomas. By comparative genomic hybridization recurrent gains of chromosomal material were found at chromosomes 7, 8, 13q, and 20 (5/17, each), while non-random losses were seen at 8p, 17p (4/17, each), and 18 (8/17 cases). Deletions at 5q, the location of the APC tumour suppressor gene, were seen in three cases. Microsatellite analysis with markers on chromosomal arms 1p, 5q, 8p, 17p, 18q, 19p, and 22q revealed a microsatellite instable phenotype in two cases and a high frequency of loss at 18q21-q22 (80%). Given the high incidence of 18q21-q22 deletions, we performed sequencing analysis of SMAD4, a downstream component of the TGFb-pathway, located at 18q21. Four tumours displayed mutations in highly conserved domains of the gene indicating disruption of TGFb-signalling. Our data reveal complex genetic alterations in sporadic small intestinal carcinomas. However, most tumours share deletions of 18q21-q22, which frequently target SMAD4. This indicates that disruption of TGFb-signalling plays a critical role in small intestinal tumorigenesis.

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“…In contrast, the diffuse type of gastric carcinoma tends to arise de novo and is infrequently associated with dysplasia or adenoma [66][67][68][69]. The sequential accumulation of alternations of APC and K-ras genes, characteristic of the colorectal adenoma-carcinoma sequence, however, does not occur frequently between adenoma and intestinal type adenocarcinoma of the stomach [27,[70][71][72][73][74][75][76][77]. There are two lines of evidence indicating that not all gastric dysplastic lesions are precursor lesions for gastric carcinoma.…”

Section: Epigenetic Alterations In Early Gastric Tumorigenesismentioning

confidence: 99%

Epigenetic alterations in gastric carcinogenesis

Choi

2005

Cell Res

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Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play important roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpG island methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesis and its relevance of clinical implications.

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Activation of c-K-ras mutations in human gastrointestinal tumors

Cited by 102 publications

References 38 publications

K‐ras mutation in helicobacter pylori‐associated chronic gastritis in patients with and without gastric cancer

K‐ras mutation in helicobacter pylori‐associated chronic gastritis in patients with and without gastric cancer

Genetics of adenocarcinomas of the small intestine: frequent deletions at chromosome 18q and mutations of the SMAD4 gene

Epigenetic alterations in gastric carcinogenesis

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