Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells

Junichi Soh, Naoki Okumura, William W. Lockwood, Hiromasa Yamamoto, Hisayuki Shigematsu, Wei Zhang, Raj Chari, David S. Shames, Ximing Tang, Calum MacAulay, Marileila Varella-Garcia, Tõnu Vooder, Ignacio I. Wistuba, Stephen Lam, Rolf Brekken, Shinichi Toyooka, John D. Minna, Wan L. Lam, Adi F. Gazdar

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Abstract

Background: Activating mutations in one allele of an oncogene (heterozygous mutations) are widely believed to be sufficient for tumorigenesis. However, mutant allele specific imbalance (MASI) has been observed in tumors and cell lines harboring mutations of oncogenes. Methodology/Principal Findings: We determined 1) mutational status, 2) copy number gains (CNGs) and 3) relative ratio between mutant and wild type alleles of KRAS, BRAF, PIK3CA and EGFR genes by direct sequencing and quantitative PCR assay in over 400 human tumors, cell lines, and xenografts of lung, colorectal, and pancreatic cancers. Examination of a public database indicated that homozygous mutations of five oncogenes were frequent (20%) in 833 cell lines of 12 tumor types. Our data indicated two major forms of MASI: 1) MASI with CNG, either complete or partial; and 2) MASI without CNG (uniparental disomy; UPD), due to complete loss of wild type allele. MASI was a frequent event in mutant EGFR (75%) and was due mainly to CNGs, while MASI, also frequent in mutant KRAS (58%), was mainly due to UPD. Mutant: wild type allelic ratios at the genomic level were precisely maintained after transcription. KRAS mutations or CNGs were significantly associated with increased ras GTPase activity, as measured by ELISA, and the two molecular changes were synergistic. Of 237 lung adenocarcinoma tumors, the small number with both KRAS mutation and CNG were associated with shortened survival. Conclusions: MASI is frequently present in mutant EGFR and KRAS tumor cells, and is associated with increased mutant allele transcription and gene activity. The frequent finding of mutations, CNGs and MASI occurring together in tumor cells indicates that these three genetic alterations, acting together, may have a greater role in the development or maintenance of the malignant phenotype than any individual alteration.

Original languageEnglish (US)
Article numbere7464
JournalPLoS One
Volume4
Issue number10
DOIs
StatePublished - Oct 14 2009

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oncogenes
Oncogenes
Tumors
Alleles
Cells
alleles
mutation
mutants
Mutation
Neoplasms
Transcription
Genes
Tumor Cell Line
ras Proteins
Heterografts
cell lines
neoplasm cells
Assays
neoplasms
Uniparental Disomy

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Soh, J., Okumura, N., Lockwood, W. W., Yamamoto, H., Shigematsu, H., Zhang, W., ... Gazdar, A. F. (2009). Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. PLoS One, 4(10), [e7464]. https://doi.org/10.1371/journal.pone.0007464

Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. / Soh, Junichi; Okumura, Naoki; Lockwood, William W.; Yamamoto, Hiromasa; Shigematsu, Hisayuki; Zhang, Wei; Chari, Raj; Shames, David S.; Tang, Ximing; MacAulay, Calum; Varella-Garcia, Marileila; Vooder, Tõnu; Wistuba, Ignacio I.; Lam, Stephen; Brekken, Rolf; Toyooka, Shinichi; Minna, John D.; Lam, Wan L.; Gazdar, Adi F.

In: PLoS One, Vol. 4, No. 10, e7464, 14.10.2009.

Research output: Contribution to journalArticle

Soh, J, Okumura, N, Lockwood, WW, Yamamoto, H, Shigematsu, H, Zhang, W, Chari, R, Shames, DS, Tang, X, MacAulay, C, Varella-Garcia, M, Vooder, T, Wistuba, II, Lam, S, Brekken, R, Toyooka, S, Minna, JD, Lam, WL & Gazdar, AF 2009, 'Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells', PLoS One, vol. 4, no. 10, e7464. https://doi.org/10.1371/journal.pone.0007464
Soh, Junichi ; Okumura, Naoki ; Lockwood, William W. ; Yamamoto, Hiromasa ; Shigematsu, Hisayuki ; Zhang, Wei ; Chari, Raj ; Shames, David S. ; Tang, Ximing ; MacAulay, Calum ; Varella-Garcia, Marileila ; Vooder, Tõnu ; Wistuba, Ignacio I. ; Lam, Stephen ; Brekken, Rolf ; Toyooka, Shinichi ; Minna, John D. ; Lam, Wan L. ; Gazdar, Adi F. / Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. In: PLoS One. 2009 ; Vol. 4, No. 10.
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abstract = "Background: Activating mutations in one allele of an oncogene (heterozygous mutations) are widely believed to be sufficient for tumorigenesis. However, mutant allele specific imbalance (MASI) has been observed in tumors and cell lines harboring mutations of oncogenes. Methodology/Principal Findings: We determined 1) mutational status, 2) copy number gains (CNGs) and 3) relative ratio between mutant and wild type alleles of KRAS, BRAF, PIK3CA and EGFR genes by direct sequencing and quantitative PCR assay in over 400 human tumors, cell lines, and xenografts of lung, colorectal, and pancreatic cancers. Examination of a public database indicated that homozygous mutations of five oncogenes were frequent (20{\%}) in 833 cell lines of 12 tumor types. Our data indicated two major forms of MASI: 1) MASI with CNG, either complete or partial; and 2) MASI without CNG (uniparental disomy; UPD), due to complete loss of wild type allele. MASI was a frequent event in mutant EGFR (75{\%}) and was due mainly to CNGs, while MASI, also frequent in mutant KRAS (58{\%}), was mainly due to UPD. Mutant: wild type allelic ratios at the genomic level were precisely maintained after transcription. KRAS mutations or CNGs were significantly associated with increased ras GTPase activity, as measured by ELISA, and the two molecular changes were synergistic. Of 237 lung adenocarcinoma tumors, the small number with both KRAS mutation and CNG were associated with shortened survival. Conclusions: MASI is frequently present in mutant EGFR and KRAS tumor cells, and is associated with increased mutant allele transcription and gene activity. The frequent finding of mutations, CNGs and MASI occurring together in tumor cells indicates that these three genetic alterations, acting together, may have a greater role in the development or maintenance of the malignant phenotype than any individual alteration.",
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T1 - Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells

AU - Soh, Junichi

AU - Okumura, Naoki

AU - Lockwood, William W.

AU - Yamamoto, Hiromasa

AU - Shigematsu, Hisayuki

AU - Zhang, Wei

AU - Chari, Raj

AU - Shames, David S.

AU - Tang, Ximing

AU - MacAulay, Calum

AU - Varella-Garcia, Marileila

AU - Vooder, Tõnu

AU - Wistuba, Ignacio I.

AU - Lam, Stephen

AU - Brekken, Rolf

AU - Toyooka, Shinichi

AU - Minna, John D.

AU - Lam, Wan L.

AU - Gazdar, Adi F.

PY - 2009/10/14

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N2 - Background: Activating mutations in one allele of an oncogene (heterozygous mutations) are widely believed to be sufficient for tumorigenesis. However, mutant allele specific imbalance (MASI) has been observed in tumors and cell lines harboring mutations of oncogenes. Methodology/Principal Findings: We determined 1) mutational status, 2) copy number gains (CNGs) and 3) relative ratio between mutant and wild type alleles of KRAS, BRAF, PIK3CA and EGFR genes by direct sequencing and quantitative PCR assay in over 400 human tumors, cell lines, and xenografts of lung, colorectal, and pancreatic cancers. Examination of a public database indicated that homozygous mutations of five oncogenes were frequent (20%) in 833 cell lines of 12 tumor types. Our data indicated two major forms of MASI: 1) MASI with CNG, either complete or partial; and 2) MASI without CNG (uniparental disomy; UPD), due to complete loss of wild type allele. MASI was a frequent event in mutant EGFR (75%) and was due mainly to CNGs, while MASI, also frequent in mutant KRAS (58%), was mainly due to UPD. Mutant: wild type allelic ratios at the genomic level were precisely maintained after transcription. KRAS mutations or CNGs were significantly associated with increased ras GTPase activity, as measured by ELISA, and the two molecular changes were synergistic. Of 237 lung adenocarcinoma tumors, the small number with both KRAS mutation and CNG were associated with shortened survival. Conclusions: MASI is frequently present in mutant EGFR and KRAS tumor cells, and is associated with increased mutant allele transcription and gene activity. The frequent finding of mutations, CNGs and MASI occurring together in tumor cells indicates that these three genetic alterations, acting together, may have a greater role in the development or maintenance of the malignant phenotype than any individual alteration.

AB - Background: Activating mutations in one allele of an oncogene (heterozygous mutations) are widely believed to be sufficient for tumorigenesis. However, mutant allele specific imbalance (MASI) has been observed in tumors and cell lines harboring mutations of oncogenes. Methodology/Principal Findings: We determined 1) mutational status, 2) copy number gains (CNGs) and 3) relative ratio between mutant and wild type alleles of KRAS, BRAF, PIK3CA and EGFR genes by direct sequencing and quantitative PCR assay in over 400 human tumors, cell lines, and xenografts of lung, colorectal, and pancreatic cancers. Examination of a public database indicated that homozygous mutations of five oncogenes were frequent (20%) in 833 cell lines of 12 tumor types. Our data indicated two major forms of MASI: 1) MASI with CNG, either complete or partial; and 2) MASI without CNG (uniparental disomy; UPD), due to complete loss of wild type allele. MASI was a frequent event in mutant EGFR (75%) and was due mainly to CNGs, while MASI, also frequent in mutant KRAS (58%), was mainly due to UPD. Mutant: wild type allelic ratios at the genomic level were precisely maintained after transcription. KRAS mutations or CNGs were significantly associated with increased ras GTPase activity, as measured by ELISA, and the two molecular changes were synergistic. Of 237 lung adenocarcinoma tumors, the small number with both KRAS mutation and CNG were associated with shortened survival. Conclusions: MASI is frequently present in mutant EGFR and KRAS tumor cells, and is associated with increased mutant allele transcription and gene activity. The frequent finding of mutations, CNGs and MASI occurring together in tumor cells indicates that these three genetic alterations, acting together, may have a greater role in the development or maintenance of the malignant phenotype than any individual alteration.

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