Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer

Montserrat Sanchez-Cespedes, Andre L. Reed, Martin Buta, Li Wu, William H. Westra, James G. Herman, Stephen C Yang, Jin Jen, David Sidransky

Research output: Contribution to journalArticle

Abstract

Inactivation of the P16 (INK4A)/retinoblastoma (RB) or TP53 biochemical pathway is frequent event in most human cancers. Recent evidence has shown that P14ARF binds to MDM2 leading to an increased availability of wild type TP53 protein. Functional studies also support a putative tumor suppressor gene function for p14(ARF) suggesting that p14(ARF) or p53 inactivation may be functionally equivalent in tumorigenesis. To study the relative contribution of each pathway in tumorigenesis, we analysed and compared alterations of the p16, p14(ARF) and p53 genes in 38 primary non-small cell lung cancers (NSCLCs) (19 adenocarcinomas and 19 squamous carcinoma). The p16 tumor suppressor gene was inactivated in 22 of 38 (58%) tumors. Twelve of these samples (31%) had homozygous deletions by microsatellite analysis; eight of them (21%) had p16 promoter hypermethylation detected by Methylation Specific PCR (MSP) and the remaining two (5%) harbored a point mutation in exon 2 by sequence analysis. The absence of P16 protein in every case was confirmed by immunohistochemistry. Fourteen of the 22 tumors with p16 inactivation also inactivated the p14(ARF) gene (12 with homozygous deletions extending into INK4a/ARF and two with exon 2 mutations). Mutations of p53 were found in 18 (47%) of the tumors and nine of them (50%) harbored p14(ARF) inactivation. Thus, an inverse correlation was not found between p14(ARF) and p53 genetic alterations (P = O.18; Fisher Exact Test). Our data confirm that the p16 gene is frequently inactivated in NSCLC. Assuming that 9p deletion occurs first, the common occurrence of p53 and p14(ARF) alterations suggests that p14(ARF) inactivation is not functionally equivalent to abrogation of the TP53 pathway by p53 mutation.

Original languageEnglish (US)
Pages (from-to)5843-5849
Number of pages7
JournalOncogene
Volume18
Issue number43
DOIs
StatePublished - Oct 21 1999

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Tumor Suppressor Protein p14ARF
Non-Small Cell Lung Carcinoma
Mutation
Tumor Suppressor Genes
Exons
Neoplasms
Carcinogenesis
Cyclin-Dependent Kinase Inhibitor p16
p16 Genes
Tumor Suppressor Protein p53
Retinoblastoma
p53 Genes
Point Mutation
Microsatellite Repeats
Methylation
Sequence Analysis
Squamous Cell Carcinoma
Adenocarcinoma
Immunohistochemistry
Polymerase Chain Reaction

Keywords

  • Non small cell lung cancer
  • p14(ARF) inactivation
  • p16 inactivation
  • p53 gene mutations

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer. / Sanchez-Cespedes, Montserrat; Reed, Andre L.; Buta, Martin; Wu, Li; Westra, William H.; Herman, James G.; Yang, Stephen C; Jen, Jin; Sidransky, David.

In: Oncogene, Vol. 18, No. 43, 21.10.1999, p. 5843-5849.

Research output: Contribution to journalArticle

Sanchez-Cespedes, M, Reed, AL, Buta, M, Wu, L, Westra, WH, Herman, JG, Yang, SC, Jen, J & Sidransky, D 1999, 'Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer', Oncogene, vol. 18, no. 43, pp. 5843-5849. https://doi.org/10.1038/sj.onc.1203003
Sanchez-Cespedes M, Reed AL, Buta M, Wu L, Westra WH, Herman JG et al. Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer. Oncogene. 1999 Oct 21;18(43):5843-5849. https://doi.org/10.1038/sj.onc.1203003
Sanchez-Cespedes, Montserrat ; Reed, Andre L. ; Buta, Martin ; Wu, Li ; Westra, William H. ; Herman, James G. ; Yang, Stephen C ; Jen, Jin ; Sidransky, David. / Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer. In: Oncogene. 1999 ; Vol. 18, No. 43. pp. 5843-5849.
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abstract = "Inactivation of the P16 (INK4A)/retinoblastoma (RB) or TP53 biochemical pathway is frequent event in most human cancers. Recent evidence has shown that P14ARF binds to MDM2 leading to an increased availability of wild type TP53 protein. Functional studies also support a putative tumor suppressor gene function for p14(ARF) suggesting that p14(ARF) or p53 inactivation may be functionally equivalent in tumorigenesis. To study the relative contribution of each pathway in tumorigenesis, we analysed and compared alterations of the p16, p14(ARF) and p53 genes in 38 primary non-small cell lung cancers (NSCLCs) (19 adenocarcinomas and 19 squamous carcinoma). The p16 tumor suppressor gene was inactivated in 22 of 38 (58{\%}) tumors. Twelve of these samples (31{\%}) had homozygous deletions by microsatellite analysis; eight of them (21{\%}) had p16 promoter hypermethylation detected by Methylation Specific PCR (MSP) and the remaining two (5{\%}) harbored a point mutation in exon 2 by sequence analysis. The absence of P16 protein in every case was confirmed by immunohistochemistry. Fourteen of the 22 tumors with p16 inactivation also inactivated the p14(ARF) gene (12 with homozygous deletions extending into INK4a/ARF and two with exon 2 mutations). Mutations of p53 were found in 18 (47{\%}) of the tumors and nine of them (50{\%}) harbored p14(ARF) inactivation. Thus, an inverse correlation was not found between p14(ARF) and p53 genetic alterations (P = O.18; Fisher Exact Test). Our data confirm that the p16 gene is frequently inactivated in NSCLC. Assuming that 9p deletion occurs first, the common occurrence of p53 and p14(ARF) alterations suggests that p14(ARF) inactivation is not functionally equivalent to abrogation of the TP53 pathway by p53 mutation.",
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AU - Wu, Li

AU - Westra, William H.

AU - Herman, James G.

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