High Frequency of Microsatellite Instability in Intestinal-type Gastric Cancer in Korean Patients

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Abstract

Background

Although there have been some reports on microsatellite alterations in gastric cancer, findings are inconsistent regarding the associations between histological classification and microsatellite instability (MSI). In the present study, we attempted to determine whether Lauren's histological subtypes are related with MSI status.

Methods

Paraffin-embedded tissue samples from 14 diffuse-type and 14 intestinal-type gastric adenocarcinomas were matched up according to patient gender and age. Mononucleotide markers ( BAT25 and BAT26) and dinucleotide markers ( D2S123, D5S346, and D17S250) were used for MSI analyses. Microsatellite genotypes were categorized in terms of high MSI incidence (MSI-H, >30% positive marker) or low MSI incidence (MSI-L, <30% positive marker). Losses of hMLH1 and hMSH2 protein expression were immunohistochemically studied.

Results

MSI-H was observed in 11 cases (78%) of the 14 intestinal-type cases as compared to 3 (21%) of the 14 diffuse-type cases ( p=0.007). In MSI-H tumors, 10 cases (71%) showed losses of hMLH1 protein expression, while 2 cases (14%) in MSI-L tumors showed losses of hMLH1 protein expression ( p=0.006).

Conclusion

MSI-H tumors are more frequently found in intestinal-type gastric cancer, which suggests the possibility that there are different pathogenic pathways in gastric carcinogenesis according to histologic type.

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Most cited references 33

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A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.

C R Boland, S Thibodeau, S Hamilton … (1998)

In December 1997, the National Cancer Institute sponsored "The International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition," to review and unify the field. The following recommendations were endorsed at the workshop. (a) The form of genomic instability associated with defective DNA mismatch repair in tumors is to be called microsatellite instability (MSI). (b) A panel of five microsatellites has been validated and is recommended as a reference panel for future research in the field. Tumors may be characterized on the basis of: high-frequency MSI (MSI-H), if two or more of the five markers show instability (i.e., have insertion/deletion mutations), and low-frequency MSI (MSI-L), if only one of the five markers shows instability. The distinction between microsatellite stable (MSS) and low frequency MSI (MSI-L) can only be accomplished if a greater number of markers is utilized. (c) A unique clinical and pathological phenotype is identified for the MSI-H tumors, which comprise approximately 15% of colorectal cancers, whereas MSI-L and MSS tumors appear to be phenotypically similar. MSI-H colorectal tumors are found predominantly in the proximal colon, have unique histopathological features, and are associated with a less aggressive clinical course than are stage-matched MSI-L or MSS tumors. Preclinical models suggest the possibility that these tumors may be resistant to the cytotoxicity induced by certain chemotherapeutic agents. The implications for MSI-L are not yet clear. (d) MSI can be measured in fresh or fixed tumor specimens equally well; microdissection of pathological specimens is recommended to enrich for neoplastic tissue; and normal tissue is required to document the presence of MSI. (e) The "Bethesda guidelines," which were developed in 1996 to assist in the selection of tumors for microsatellite analysis, are endorsed. (f) The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms. (g) A research agenda was recommended.

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Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis.

Y Ionov, M A Peinado, S Malkhosyan … (1993)

Spontaneous errors in DNA replication have been suggested to play a significant role in neoplastic transformation and to explain the chromosomal alterations seen in cancer cells. A defective replication factor could increase the mutation rate in clonal variants arising during tumour progression, but despite intensive efforts, increases in tumour cell mutation rates have not been unambiguously shown. Here we use an unbiased genomic fingerprinting technique to show that 12 per cent of colorectal carcinomas carry somatic deletions in poly(dA.dT) sequences and other simple repeats. We estimate that cells from these tumours can carry more than 100,000 such mutations. Only tumours with affected poly(dA.dT) sequences carry mutations in the other simple repeats examined, and such mutations can be found in all neoplastic regions of multiple tumours from the same patient, including adenomas. Tumours with these mutations show distinctive genotypic and phenotypic features. We conclude that these mutations reflect a previously undescribed form of carcinogenesis in the colon (predisposition to which may be inherited) mediated by a mutation in a DNA replication factor resulting in reduced fidelity for replication or repair (a 'mutator mutation').

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Clues to the pathogenesis of familial colorectal cancer.

Jin Jen, Ian Hamilton, Päivi Peltomäki … (1993)

A predisposition to colorectal cancer is shown to be linked to markers on chromosome 2 in some families. Molecular features of "familial" cancers were compared with those of sporadic colon cancers. Neither the familial nor sporadic cancers showed loss of heterozygosity for chromosome 2 markers, and the incidence of mutations in KRAS, P53, and APC was similar in the two groups of tumors. Most of the familial cancers, however, had widespread alterations in short repeated DNA sequences, suggesting that numerous replication errors had occurred during tumor development. Thirteen percent of sporadic cancers had identical abnormalities and these cancers shared biologic properties with the familial cases. These data suggest a mechanism for familial tumorigenesis different from that mediated by classic tumor suppressor genes.

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Author and article information

Journal

Journal ID (nlm-ta): Korean J Intern Med

Journal ID (iso-abbrev): Korean J. Intern. Med

Journal ID (publisher-id): KJIM

Title: The Korean Journal of Internal Medicine

Publisher: The Korean Association of Internal Medicine

ISSN (Print): 1226-3303

ISSN (Electronic): 2005-6648

Publication date (Print): June 2005

Publication date (Electronic): 30 June 2005

Volume: 20

Issue: 2

Pages: 116-122

Affiliations

Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

[2 ]Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

[3 ]Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Author notes

Correspondence to: Jae J. Kim, M.D., Ph.D., Department of Internal Medicine, Samsung Medical Center, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, Korea. Tel: 82-2-3410-3409, Fax: 82-2-3410-3849, jjkim@ 123456smc.samsung.co.kr

Article

DOI: 10.3904/kjim.2005.20.2.116

PMC ID: 3891379

PubMed ID: 16134765

SO-VID: ac149e50-09da-45d6-ac78-079d4fd48961

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

High Frequency of Microsatellite Instability in Intestinal-type Gastric Cancer in Korean Patients

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Abstract

Background

Methods

Results

Conclusion

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Karger: Oncology

Most cited references 33

A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.

Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis.

Clues to the pathogenesis of familial colorectal cancer.

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