Unfavorable Prognostic Factors Associated with High Frequency of Microsatellite Instability and Comparative Genomic Hybridization Analysis in Endometrial Cancer

Akira Hirasawa, Daisuke Aoki, Jun Inoue, Issei Imoto, Nobuyuki Susumu, Kokichi Sugano, Shiro Nozawa, Johji Inazawa

Research output: Contribution to journalArticle

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Abstract

Purpose: Although many articles have been published regarding chromosomal instability (CI) and microsatellite instability (MI) in endometrial adenocarcinoma, the relationship between prognostic factors and the biological mechanisms accounting for genetic instability in these tumors has not yet been precisely defined. To do that, it will be necessary to clarify the molecular mechanisms involved in endometrial carcinogenesis. Experimental Design: Tissue samples from 43 human primary endometrioid endometrial adenocarcinomas (EACs) were analyzed for CI and MI status using comparative genomic hybridization and 11 microsatellite loci, respectively. Methylation status of the promoter of MLH1 was also determined. We analyzed all three of these parameters in relation to each other and to clinicopathological factors. Results: Sixty-five percent of the EACs we examined had detectable CI. Frequent copy number gains were seen at 1q25-41 (23%), 8q11.1-q21.1 (23%), 8q21.3-qter (21%); 28% of these tumors exhibited high-frequency MI (MSI-H); Methylation of the MLH1 promoter was observed in 92% of EACs with MSI-H. Southern blotting showed amplification of MYCN in one tumor, which has been documented for the first time in a primary human EAC. Conclusions: MSI-H was correlated with histological grade, International Federation of Gynecologists and Obstetricians (FIGO) stage, myometrial invasion, and lymphonode metastasis. Our comparative genomic hybridization results demonstrated that the number of chromosomes involved in genomic alterations in EACs was distinctively fewer than those in other types of tumor. The carcinogenetic process leading to EAC appears to be highly complex; for example, MI and CI may act synergistically, whereas CI and/or MI are likely to be linked with tumor heterogeneity.

Original languageEnglish
Pages (from-to)5675-5682
Number of pages8
JournalClinical Cancer Research
Volume9
Issue number15
Publication statusPublished - 2003 Nov 15

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Microsatellite Instability
Comparative Genomic Hybridization
Endometrial Neoplasms
Chromosomal Instability
Adenocarcinoma
Neoplasms
Methylation
Endometrioid Carcinoma
Southern Blotting
Microsatellite Repeats
Carcinogenesis
Research Design
Chromosomes
Neoplasm Metastasis
N-methylsuccinimide

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Unfavorable Prognostic Factors Associated with High Frequency of Microsatellite Instability and Comparative Genomic Hybridization Analysis in Endometrial Cancer. / Hirasawa, Akira; Aoki, Daisuke; Inoue, Jun; Imoto, Issei; Susumu, Nobuyuki; Sugano, Kokichi; Nozawa, Shiro; Inazawa, Johji.

In: Clinical Cancer Research, Vol. 9, No. 15, 15.11.2003, p. 5675-5682.

Research output: Contribution to journalArticle

Hirasawa, Akira ; Aoki, Daisuke ; Inoue, Jun ; Imoto, Issei ; Susumu, Nobuyuki ; Sugano, Kokichi ; Nozawa, Shiro ; Inazawa, Johji. / Unfavorable Prognostic Factors Associated with High Frequency of Microsatellite Instability and Comparative Genomic Hybridization Analysis in Endometrial Cancer. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 15. pp. 5675-5682.
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T1 - Unfavorable Prognostic Factors Associated with High Frequency of Microsatellite Instability and Comparative Genomic Hybridization Analysis in Endometrial Cancer

AU - Hirasawa, Akira

AU - Aoki, Daisuke

AU - Inoue, Jun

AU - Imoto, Issei

AU - Susumu, Nobuyuki

AU - Sugano, Kokichi

AU - Nozawa, Shiro

AU - Inazawa, Johji

PY - 2003/11/15

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N2 - Purpose: Although many articles have been published regarding chromosomal instability (CI) and microsatellite instability (MI) in endometrial adenocarcinoma, the relationship between prognostic factors and the biological mechanisms accounting for genetic instability in these tumors has not yet been precisely defined. To do that, it will be necessary to clarify the molecular mechanisms involved in endometrial carcinogenesis. Experimental Design: Tissue samples from 43 human primary endometrioid endometrial adenocarcinomas (EACs) were analyzed for CI and MI status using comparative genomic hybridization and 11 microsatellite loci, respectively. Methylation status of the promoter of MLH1 was also determined. We analyzed all three of these parameters in relation to each other and to clinicopathological factors. Results: Sixty-five percent of the EACs we examined had detectable CI. Frequent copy number gains were seen at 1q25-41 (23%), 8q11.1-q21.1 (23%), 8q21.3-qter (21%); 28% of these tumors exhibited high-frequency MI (MSI-H); Methylation of the MLH1 promoter was observed in 92% of EACs with MSI-H. Southern blotting showed amplification of MYCN in one tumor, which has been documented for the first time in a primary human EAC. Conclusions: MSI-H was correlated with histological grade, International Federation of Gynecologists and Obstetricians (FIGO) stage, myometrial invasion, and lymphonode metastasis. Our comparative genomic hybridization results demonstrated that the number of chromosomes involved in genomic alterations in EACs was distinctively fewer than those in other types of tumor. The carcinogenetic process leading to EAC appears to be highly complex; for example, MI and CI may act synergistically, whereas CI and/or MI are likely to be linked with tumor heterogeneity.

AB - Purpose: Although many articles have been published regarding chromosomal instability (CI) and microsatellite instability (MI) in endometrial adenocarcinoma, the relationship between prognostic factors and the biological mechanisms accounting for genetic instability in these tumors has not yet been precisely defined. To do that, it will be necessary to clarify the molecular mechanisms involved in endometrial carcinogenesis. Experimental Design: Tissue samples from 43 human primary endometrioid endometrial adenocarcinomas (EACs) were analyzed for CI and MI status using comparative genomic hybridization and 11 microsatellite loci, respectively. Methylation status of the promoter of MLH1 was also determined. We analyzed all three of these parameters in relation to each other and to clinicopathological factors. Results: Sixty-five percent of the EACs we examined had detectable CI. Frequent copy number gains were seen at 1q25-41 (23%), 8q11.1-q21.1 (23%), 8q21.3-qter (21%); 28% of these tumors exhibited high-frequency MI (MSI-H); Methylation of the MLH1 promoter was observed in 92% of EACs with MSI-H. Southern blotting showed amplification of MYCN in one tumor, which has been documented for the first time in a primary human EAC. Conclusions: MSI-H was correlated with histological grade, International Federation of Gynecologists and Obstetricians (FIGO) stage, myometrial invasion, and lymphonode metastasis. Our comparative genomic hybridization results demonstrated that the number of chromosomes involved in genomic alterations in EACs was distinctively fewer than those in other types of tumor. The carcinogenetic process leading to EAC appears to be highly complex; for example, MI and CI may act synergistically, whereas CI and/or MI are likely to be linked with tumor heterogeneity.

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