Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage

Kazuhiko Nakagawa, Nicholas K. Conrad, John P. Williams, Bruce E. Johnson, Michael J. Kelley

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

The CDKN2 tumor suppressor gene encodes an inhibitor of type D cyclin dependent kinases. CDKN2 is homozygously deleted in approximately 25% of non-small cell lung cancer (NSCLC) cell lines and these deletions are associated with advanced stage cancer. Conflicting reports of the frequency of CDKN2 alterations in NSCLC tumors prompted us to examine the relationship of these alterations and those of the related gene, MTS2, with patient stage and site of cancer. One hundred twenty-five NSCLC samples (71 cell lines and 54 tumors) were examined by PCR-SSCP. Twenty of 71 (28%) tumor cell lines had homozygous deletions, and six (8%) had point mutations compared to 4 (7%) with point mutations among 54 tumor samples. All mutations were observed in tumors or cell lines from patients with stage III or IV disease. Two patients with no mutations in their primary tumor had a CDKN2 point mutation detected in a metastatic tumor. Point mutations were G:C to T:A transversion on the coding strand in five of 10 and resulted in nonsense mutations in seven of 10. Undetectable CDKN2 mRNA, in the absence of detectable genetic alteration, was noted in a similar fraction of cell lines derived from patients with stage I or II disease [two of seven (29%)) and stage III or IV disease [15 of 49 (31%)]. Homozygous deletion of MTS2 was found in 17 of 20 cell lines with CDKN2 deletions; no point mutations of MTS2 were identified by SSCP in the 125 samples. Thus, CDKN2 is a frequent target of genetic alterations at 9p21 in NSCLC. Both deletions and point mutations of CDKN2 are closely associated with tumor dissemination.

Original languageEnglish (US)
Pages (from-to)1842-1851
Number of pages10
JournalOncogene
Volume11
Issue number9
StatePublished - Nov 2 1995

Fingerprint

Non-Small Cell Lung Carcinoma
Point Mutation
Tumor Cell Line
Neoplasms
Single-Stranded Conformational Polymorphism
Cell Line
Cyclin D
Mutation
Cyclin-Dependent Kinases
Nonsense Codon
Sequence Deletion
Tumor Suppressor Genes
Polymerase Chain Reaction
Messenger RNA
Genes

Keywords

  • CDKN2
  • Lung neoplasm
  • p15
  • p16
  • Point mutation

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

Nakagawa, K., Conrad, N. K., Williams, J. P., Johnson, B. E., & Kelley, M. J. (1995). Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage. Oncogene, 11(9), 1842-1851.

Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage. / Nakagawa, Kazuhiko; Conrad, Nicholas K.; Williams, John P.; Johnson, Bruce E.; Kelley, Michael J.

In: Oncogene, Vol. 11, No. 9, 02.11.1995, p. 1842-1851.

Research output: Contribution to journalArticle

Nakagawa, K, Conrad, NK, Williams, JP, Johnson, BE & Kelley, MJ 1995, 'Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage', Oncogene, vol. 11, no. 9, pp. 1842-1851.
Nakagawa, Kazuhiko ; Conrad, Nicholas K. ; Williams, John P. ; Johnson, Bruce E. ; Kelley, Michael J. / Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage. In: Oncogene. 1995 ; Vol. 11, No. 9. pp. 1842-1851.
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