Loss of heterozygosity of chromosome 12p does not correlate with KRAS mutation in non-small cell lung cancer

Mika Uchiyama, Noriyasu Usami, Masashi Kondo, Shoichi Mori, Masao Ito, Genshi Ito, Hiromu Yoshioka, Munehisa Imaizumi, Yuichi Ueda, Masahide Takahashi, John D. Minna, Kaoru Shimokata, Yoshitaka Sekido

Research output: Contribution to journalArticle

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Abstract

Activating mutations of RAS gene families have been found in a variety of human malignancies, including lung cancer, suggesting their dominant role in tumorigenesis. However, several studies have shown a frequent loss of the wild-type KRAS allele in the tumors of murine models and an inhibition of oncogenic phenotype in tumor cell lines by transfection of wild-type RAS, indicating that wild-type RAS may have oncosuppressive properties. To determine whether loss of wild-type KRAS is involved in the development of human lung cancer, we investigated the mutations of KRAS, NRAS and BRAF in 154 primary non-small cell lung cancers (NSCLCs) as well as 10 NSCLC cell lines that have been shown to have KRAS mutations. We also determined the loss of heterozygosity status of KRAS alleles in these tumors. We detected point mutations of KRAS in 11 (7%) of 154 NSCLCs, with 10 cases at codon 12 and 1 at codon 61, but no mutations of NRAS or BRAF were found. Using the laser capture microdissection technique, we confirmed that 9 of the 11 tumors and 7 of the 10 NSCLC cell lines retained the wild-type KRAS allele. Among the cell lines with heterozygosity of mutant and wild-type KRAS, all of the cell lines tested for expression were shown to express more mutated KRAS than wild-type mRNA, with higher amounts of KRAS protein also being expressed compared to the cell lines with a loss of wild-type KRAS allele. In addition, among 148 specimens available for immunohistochemical analysis, 113 (76%) showed positive staining of KRAS, indicating that the vast majority of NSCLCs continue to express wild-type KRAS. Our findings indicate that the wild-type KRAS allele is occasionally lost in human lung cancer, and that the oncogenic activation of mutant KRAS is more frequently associated with an overexpression of the mutant allele than with a loss of the wild-type allele in human NSCLC development.

Original languageEnglish
Pages (from-to)962-969
Number of pages8
JournalInternational Journal of Cancer
Volume107
Issue number6
DOIs
Publication statusPublished - 20-12-2003

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Loss of Heterozygosity
Non-Small Cell Lung Carcinoma
Chromosomes
Alleles
Mutation
Cell Line
Lung Neoplasms
Codon
Neoplasms
Laser Capture Microdissection
Human Development
Tumor Cell Line
Point Mutation
Transfection
Carcinogenesis
Staining and Labeling
Phenotype
Messenger RNA
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Uchiyama, Mika ; Usami, Noriyasu ; Kondo, Masashi ; Mori, Shoichi ; Ito, Masao ; Ito, Genshi ; Yoshioka, Hiromu ; Imaizumi, Munehisa ; Ueda, Yuichi ; Takahashi, Masahide ; Minna, John D. ; Shimokata, Kaoru ; Sekido, Yoshitaka. / Loss of heterozygosity of chromosome 12p does not correlate with KRAS mutation in non-small cell lung cancer. In: International Journal of Cancer. 2003 ; Vol. 107, No. 6. pp. 962-969.
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title = "Loss of heterozygosity of chromosome 12p does not correlate with KRAS mutation in non-small cell lung cancer",
abstract = "Activating mutations of RAS gene families have been found in a variety of human malignancies, including lung cancer, suggesting their dominant role in tumorigenesis. However, several studies have shown a frequent loss of the wild-type KRAS allele in the tumors of murine models and an inhibition of oncogenic phenotype in tumor cell lines by transfection of wild-type RAS, indicating that wild-type RAS may have oncosuppressive properties. To determine whether loss of wild-type KRAS is involved in the development of human lung cancer, we investigated the mutations of KRAS, NRAS and BRAF in 154 primary non-small cell lung cancers (NSCLCs) as well as 10 NSCLC cell lines that have been shown to have KRAS mutations. We also determined the loss of heterozygosity status of KRAS alleles in these tumors. We detected point mutations of KRAS in 11 (7{\%}) of 154 NSCLCs, with 10 cases at codon 12 and 1 at codon 61, but no mutations of NRAS or BRAF were found. Using the laser capture microdissection technique, we confirmed that 9 of the 11 tumors and 7 of the 10 NSCLC cell lines retained the wild-type KRAS allele. Among the cell lines with heterozygosity of mutant and wild-type KRAS, all of the cell lines tested for expression were shown to express more mutated KRAS than wild-type mRNA, with higher amounts of KRAS protein also being expressed compared to the cell lines with a loss of wild-type KRAS allele. In addition, among 148 specimens available for immunohistochemical analysis, 113 (76{\%}) showed positive staining of KRAS, indicating that the vast majority of NSCLCs continue to express wild-type KRAS. Our findings indicate that the wild-type KRAS allele is occasionally lost in human lung cancer, and that the oncogenic activation of mutant KRAS is more frequently associated with an overexpression of the mutant allele than with a loss of the wild-type allele in human NSCLC development.",
author = "Mika Uchiyama and Noriyasu Usami and Masashi Kondo and Shoichi Mori and Masao Ito and Genshi Ito and Hiromu Yoshioka and Munehisa Imaizumi and Yuichi Ueda and Masahide Takahashi and Minna, {John D.} and Kaoru Shimokata and Yoshitaka Sekido",
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Uchiyama, M, Usami, N, Kondo, M, Mori, S, Ito, M, Ito, G, Yoshioka, H, Imaizumi, M, Ueda, Y, Takahashi, M, Minna, JD, Shimokata, K & Sekido, Y 2003, 'Loss of heterozygosity of chromosome 12p does not correlate with KRAS mutation in non-small cell lung cancer', International Journal of Cancer, vol. 107, no. 6, pp. 962-969. https://doi.org/10.1002/ijc.11493

Loss of heterozygosity of chromosome 12p does not correlate with KRAS mutation in non-small cell lung cancer. / Uchiyama, Mika; Usami, Noriyasu; Kondo, Masashi; Mori, Shoichi; Ito, Masao; Ito, Genshi; Yoshioka, Hiromu; Imaizumi, Munehisa; Ueda, Yuichi; Takahashi, Masahide; Minna, John D.; Shimokata, Kaoru; Sekido, Yoshitaka.

In: International Journal of Cancer, Vol. 107, No. 6, 20.12.2003, p. 962-969.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Loss of heterozygosity of chromosome 12p does not correlate with KRAS mutation in non-small cell lung cancer

AU - Uchiyama, Mika

AU - Usami, Noriyasu

AU - Kondo, Masashi

AU - Mori, Shoichi

AU - Ito, Masao

AU - Ito, Genshi

AU - Yoshioka, Hiromu

AU - Imaizumi, Munehisa

AU - Ueda, Yuichi

AU - Takahashi, Masahide

AU - Minna, John D.

AU - Shimokata, Kaoru

AU - Sekido, Yoshitaka

PY - 2003/12/20

Y1 - 2003/12/20

N2 - Activating mutations of RAS gene families have been found in a variety of human malignancies, including lung cancer, suggesting their dominant role in tumorigenesis. However, several studies have shown a frequent loss of the wild-type KRAS allele in the tumors of murine models and an inhibition of oncogenic phenotype in tumor cell lines by transfection of wild-type RAS, indicating that wild-type RAS may have oncosuppressive properties. To determine whether loss of wild-type KRAS is involved in the development of human lung cancer, we investigated the mutations of KRAS, NRAS and BRAF in 154 primary non-small cell lung cancers (NSCLCs) as well as 10 NSCLC cell lines that have been shown to have KRAS mutations. We also determined the loss of heterozygosity status of KRAS alleles in these tumors. We detected point mutations of KRAS in 11 (7%) of 154 NSCLCs, with 10 cases at codon 12 and 1 at codon 61, but no mutations of NRAS or BRAF were found. Using the laser capture microdissection technique, we confirmed that 9 of the 11 tumors and 7 of the 10 NSCLC cell lines retained the wild-type KRAS allele. Among the cell lines with heterozygosity of mutant and wild-type KRAS, all of the cell lines tested for expression were shown to express more mutated KRAS than wild-type mRNA, with higher amounts of KRAS protein also being expressed compared to the cell lines with a loss of wild-type KRAS allele. In addition, among 148 specimens available for immunohistochemical analysis, 113 (76%) showed positive staining of KRAS, indicating that the vast majority of NSCLCs continue to express wild-type KRAS. Our findings indicate that the wild-type KRAS allele is occasionally lost in human lung cancer, and that the oncogenic activation of mutant KRAS is more frequently associated with an overexpression of the mutant allele than with a loss of the wild-type allele in human NSCLC development.

AB - Activating mutations of RAS gene families have been found in a variety of human malignancies, including lung cancer, suggesting their dominant role in tumorigenesis. However, several studies have shown a frequent loss of the wild-type KRAS allele in the tumors of murine models and an inhibition of oncogenic phenotype in tumor cell lines by transfection of wild-type RAS, indicating that wild-type RAS may have oncosuppressive properties. To determine whether loss of wild-type KRAS is involved in the development of human lung cancer, we investigated the mutations of KRAS, NRAS and BRAF in 154 primary non-small cell lung cancers (NSCLCs) as well as 10 NSCLC cell lines that have been shown to have KRAS mutations. We also determined the loss of heterozygosity status of KRAS alleles in these tumors. We detected point mutations of KRAS in 11 (7%) of 154 NSCLCs, with 10 cases at codon 12 and 1 at codon 61, but no mutations of NRAS or BRAF were found. Using the laser capture microdissection technique, we confirmed that 9 of the 11 tumors and 7 of the 10 NSCLC cell lines retained the wild-type KRAS allele. Among the cell lines with heterozygosity of mutant and wild-type KRAS, all of the cell lines tested for expression were shown to express more mutated KRAS than wild-type mRNA, with higher amounts of KRAS protein also being expressed compared to the cell lines with a loss of wild-type KRAS allele. In addition, among 148 specimens available for immunohistochemical analysis, 113 (76%) showed positive staining of KRAS, indicating that the vast majority of NSCLCs continue to express wild-type KRAS. Our findings indicate that the wild-type KRAS allele is occasionally lost in human lung cancer, and that the oncogenic activation of mutant KRAS is more frequently associated with an overexpression of the mutant allele than with a loss of the wild-type allele in human NSCLC development.

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