Both gene amplification and allelic loss occur at 14q13.3 in lung cancer

Thomas M. Harris, Qiulu Pan, Juan Sironi, Dionne Lutz, Jianmin Tian, Jana Sapkar, Roman Perez-Soler, Steven Keller, Joseph Locker

Research output: Contribution to journalArticle

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Abstract

Purpose: Because loss of Nkx2-8 increases lung cancer in the mouse, we studied suppressive mechanisms in human lung cancer. Experimental Design: NKX2-8 is located within 14q13.3, adjacent to its close relative TTF1/NKX2-1. We first analyzed LOH of 14q13.3 in forty-five matched human lung cancer and control specimens. DNA from tumors with LOH was then analyzed with high-density single-nucleotide polymorphism (SNP) arrays. For correlation with this genetic analysis, we quantified expression of Nkx2-8 and TTF1 mRNA in tumors. Finally, suppressive function of Nkx2-8 was assessed via colony formation assays in five lung cancer cell lines. Results: Thirteen of forty-five (29%) tumors had LOH. In six tumors, most adenocarcinomas, LOH was caused by gene amplification. The 0.8-Mb common region of amplification included MBIP, SFTA, TTF1, NKX2-8, and PAX9. In 4 squamous or adenosquamous cancers, LOH was caused by deletion. In three other tumors, LOH resulted from whole chromosome mechanisms (14 -, 14+, or aneuploidy). The 1.2-Mb common region of deletion included MBIP, SFTA, TTF1, NKX2-8, PAX9, SLC25A21, and MIPOL1. Most tumors had low expression of Nkx2-8. Nevertheless, sequencing did not show NKX2-8 mutations that could explain the low expression. TTF1 overexpression, in contrast, was common and usually independent of Nkx2-8 expression. Finally, stable transfection of Nkx2-8 selectively inhibited growth of H522 lung cancer cells. Conclusions: 14q13.3, which contains NKX2-8, is subject to both amplification and deletion in lung cancer. Most tumors have low expression of Nkx2-8, and its expression can inhibit growth of some lung cancer cells.

Original languageEnglish (US)
Pages (from-to)690-699
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number4
DOIs
StatePublished - Feb 15 2011

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Gene Amplification
Loss of Heterozygosity
Lung Neoplasms
Neoplasms
Chromosomes, Human, Pair 14
Aneuploidy
Growth
Single Nucleotide Polymorphism
Transfection
Adenocarcinoma
Research Design
Cell Line
Messenger RNA
Mutation
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Both gene amplification and allelic loss occur at 14q13.3 in lung cancer. / Harris, Thomas M.; Pan, Qiulu; Sironi, Juan; Lutz, Dionne; Tian, Jianmin; Sapkar, Jana; Perez-Soler, Roman; Keller, Steven; Locker, Joseph.

In: Clinical Cancer Research, Vol. 17, No. 4, 15.02.2011, p. 690-699.

Research output: Contribution to journalArticle

Harris, TM, Pan, Q, Sironi, J, Lutz, D, Tian, J, Sapkar, J, Perez-Soler, R, Keller, S & Locker, J 2011, 'Both gene amplification and allelic loss occur at 14q13.3 in lung cancer', Clinical Cancer Research, vol. 17, no. 4, pp. 690-699. https://doi.org/10.1158/1078-0432.CCR-10-1892
Harris, Thomas M. ; Pan, Qiulu ; Sironi, Juan ; Lutz, Dionne ; Tian, Jianmin ; Sapkar, Jana ; Perez-Soler, Roman ; Keller, Steven ; Locker, Joseph. / Both gene amplification and allelic loss occur at 14q13.3 in lung cancer. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 4. pp. 690-699.
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abstract = "Purpose: Because loss of Nkx2-8 increases lung cancer in the mouse, we studied suppressive mechanisms in human lung cancer. Experimental Design: NKX2-8 is located within 14q13.3, adjacent to its close relative TTF1/NKX2-1. We first analyzed LOH of 14q13.3 in forty-five matched human lung cancer and control specimens. DNA from tumors with LOH was then analyzed with high-density single-nucleotide polymorphism (SNP) arrays. For correlation with this genetic analysis, we quantified expression of Nkx2-8 and TTF1 mRNA in tumors. Finally, suppressive function of Nkx2-8 was assessed via colony formation assays in five lung cancer cell lines. Results: Thirteen of forty-five (29{\%}) tumors had LOH. In six tumors, most adenocarcinomas, LOH was caused by gene amplification. The 0.8-Mb common region of amplification included MBIP, SFTA, TTF1, NKX2-8, and PAX9. In 4 squamous or adenosquamous cancers, LOH was caused by deletion. In three other tumors, LOH resulted from whole chromosome mechanisms (14 -, 14+, or aneuploidy). The 1.2-Mb common region of deletion included MBIP, SFTA, TTF1, NKX2-8, PAX9, SLC25A21, and MIPOL1. Most tumors had low expression of Nkx2-8. Nevertheless, sequencing did not show NKX2-8 mutations that could explain the low expression. TTF1 overexpression, in contrast, was common and usually independent of Nkx2-8 expression. Finally, stable transfection of Nkx2-8 selectively inhibited growth of H522 lung cancer cells. Conclusions: 14q13.3, which contains NKX2-8, is subject to both amplification and deletion in lung cancer. Most tumors have low expression of Nkx2-8, and its expression can inhibit growth of some lung cancer cells.",
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AU - Harris, Thomas M.

AU - Pan, Qiulu

AU - Sironi, Juan

AU - Lutz, Dionne

AU - Tian, Jianmin

AU - Sapkar, Jana

AU - Perez-Soler, Roman

AU - Keller, Steven

AU - Locker, Joseph

PY - 2011/2/15

Y1 - 2011/2/15

N2 - Purpose: Because loss of Nkx2-8 increases lung cancer in the mouse, we studied suppressive mechanisms in human lung cancer. Experimental Design: NKX2-8 is located within 14q13.3, adjacent to its close relative TTF1/NKX2-1. We first analyzed LOH of 14q13.3 in forty-five matched human lung cancer and control specimens. DNA from tumors with LOH was then analyzed with high-density single-nucleotide polymorphism (SNP) arrays. For correlation with this genetic analysis, we quantified expression of Nkx2-8 and TTF1 mRNA in tumors. Finally, suppressive function of Nkx2-8 was assessed via colony formation assays in five lung cancer cell lines. Results: Thirteen of forty-five (29%) tumors had LOH. In six tumors, most adenocarcinomas, LOH was caused by gene amplification. The 0.8-Mb common region of amplification included MBIP, SFTA, TTF1, NKX2-8, and PAX9. In 4 squamous or adenosquamous cancers, LOH was caused by deletion. In three other tumors, LOH resulted from whole chromosome mechanisms (14 -, 14+, or aneuploidy). The 1.2-Mb common region of deletion included MBIP, SFTA, TTF1, NKX2-8, PAX9, SLC25A21, and MIPOL1. Most tumors had low expression of Nkx2-8. Nevertheless, sequencing did not show NKX2-8 mutations that could explain the low expression. TTF1 overexpression, in contrast, was common and usually independent of Nkx2-8 expression. Finally, stable transfection of Nkx2-8 selectively inhibited growth of H522 lung cancer cells. Conclusions: 14q13.3, which contains NKX2-8, is subject to both amplification and deletion in lung cancer. Most tumors have low expression of Nkx2-8, and its expression can inhibit growth of some lung cancer cells.

AB - Purpose: Because loss of Nkx2-8 increases lung cancer in the mouse, we studied suppressive mechanisms in human lung cancer. Experimental Design: NKX2-8 is located within 14q13.3, adjacent to its close relative TTF1/NKX2-1. We first analyzed LOH of 14q13.3 in forty-five matched human lung cancer and control specimens. DNA from tumors with LOH was then analyzed with high-density single-nucleotide polymorphism (SNP) arrays. For correlation with this genetic analysis, we quantified expression of Nkx2-8 and TTF1 mRNA in tumors. Finally, suppressive function of Nkx2-8 was assessed via colony formation assays in five lung cancer cell lines. Results: Thirteen of forty-five (29%) tumors had LOH. In six tumors, most adenocarcinomas, LOH was caused by gene amplification. The 0.8-Mb common region of amplification included MBIP, SFTA, TTF1, NKX2-8, and PAX9. In 4 squamous or adenosquamous cancers, LOH was caused by deletion. In three other tumors, LOH resulted from whole chromosome mechanisms (14 -, 14+, or aneuploidy). The 1.2-Mb common region of deletion included MBIP, SFTA, TTF1, NKX2-8, PAX9, SLC25A21, and MIPOL1. Most tumors had low expression of Nkx2-8. Nevertheless, sequencing did not show NKX2-8 mutations that could explain the low expression. TTF1 overexpression, in contrast, was common and usually independent of Nkx2-8 expression. Finally, stable transfection of Nkx2-8 selectively inhibited growth of H522 lung cancer cells. Conclusions: 14q13.3, which contains NKX2-8, is subject to both amplification and deletion in lung cancer. Most tumors have low expression of Nkx2-8, and its expression can inhibit growth of some lung cancer cells.

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