Heterozygosity loss at 22q and lack of INI1 gene mutation in gastrointestinal stromal tumor

Research output: Contribution to journalArticle

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Abstract

Objectives: Gastrointestinal stromal tumor (GIST) is characterized by KIT or PDGFRA gene mutation. Although chromosomal losses of 22q are frequent in GIST, it is unclear which tumor suppressor genes might be inactivated in association with such losses. The INI1 gene, located at 22q11.23, is a tumor suppressor gene that is frequently altered in malignant rhabdoid tumor. Methods: To elucidate the hypothesis that the INI1 gene might be altered along with 22q loss in GIST, we examined the loss of heterozygosity (LOH) at 22q11.23, homozygous deletion and mutation of the INI1 gene, and its gene product expression as well as mutations of KIT and PDGFRA in 27 cases of GIST. Results: Among the 27 informative cases, 19 (70.4%) showed LOH of at least one of the microsatellite markers on 22q11.23. None of the cases (0%) showed homozygous deletion or mutation of the INI1 gene. Immunohistochemically, the INI1 expression was focally reduced in 17/27 (63%) cases, and the INI1 protein level and INI1 mRNA level were each correlated with the presence of 22q11.23 LOH. Although the 22q11.23 LOH was more frequently present in high- than in low-grade tumors, INI1 expression level was not correlated with tumor grade, tumor size, proliferative activity and the expression levels of cyclin D1 and p16INK4a. KIT mutations were found in 18/27 (66.7%) GISTs; however, the KIT genotype was not correlated with the status of LOH at 22q11.23. Conclusions: The results suggest that 22q11.23 LOH is frequently present in GIST irrespective of KIT genotype and it might play a role in part of the development of GIST. However, the hemiallelic loss of INI1 gene causing reduced expression of INI1 protein probably does not have a major impact in the progression of GIST.

Original languageEnglish
Pages (from-to)132-139
Number of pages8
JournalPathobiology
Volume78
Issue number3
DOIs
Publication statusPublished - Jun 1 2011

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Gastrointestinal Stromal Tumors
Loss of Heterozygosity
Mutation
Genes
Sequence Deletion
Tumor Suppressor Genes
Genotype
Rhabdoid Tumor
Neoplasms
Cyclin D1
Microsatellite Repeats
Proteins
Gene Expression
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Heterozygosity loss at 22q and lack of INI1 gene mutation in gastrointestinal stromal tumor. / Yamamoto, Hidetaka; Kohashi, Kenichi; Tsuneyoshi, Masazumi; Oda, Yoshinao.

In: Pathobiology, Vol. 78, No. 3, 01.06.2011, p. 132-139.

Research output: Contribution to journalArticle

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abstract = "Objectives: Gastrointestinal stromal tumor (GIST) is characterized by KIT or PDGFRA gene mutation. Although chromosomal losses of 22q are frequent in GIST, it is unclear which tumor suppressor genes might be inactivated in association with such losses. The INI1 gene, located at 22q11.23, is a tumor suppressor gene that is frequently altered in malignant rhabdoid tumor. Methods: To elucidate the hypothesis that the INI1 gene might be altered along with 22q loss in GIST, we examined the loss of heterozygosity (LOH) at 22q11.23, homozygous deletion and mutation of the INI1 gene, and its gene product expression as well as mutations of KIT and PDGFRA in 27 cases of GIST. Results: Among the 27 informative cases, 19 (70.4{\%}) showed LOH of at least one of the microsatellite markers on 22q11.23. None of the cases (0{\%}) showed homozygous deletion or mutation of the INI1 gene. Immunohistochemically, the INI1 expression was focally reduced in 17/27 (63{\%}) cases, and the INI1 protein level and INI1 mRNA level were each correlated with the presence of 22q11.23 LOH. Although the 22q11.23 LOH was more frequently present in high- than in low-grade tumors, INI1 expression level was not correlated with tumor grade, tumor size, proliferative activity and the expression levels of cyclin D1 and p16INK4a. KIT mutations were found in 18/27 (66.7{\%}) GISTs; however, the KIT genotype was not correlated with the status of LOH at 22q11.23. Conclusions: The results suggest that 22q11.23 LOH is frequently present in GIST irrespective of KIT genotype and it might play a role in part of the development of GIST. However, the hemiallelic loss of INI1 gene causing reduced expression of INI1 protein probably does not have a major impact in the progression of GIST.",
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