CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small-cell lung cancer

Kit Tam, Wei Zhang, Junichi Soh, Victor Stastny, Min Chen, Han Sun, Kelsie Thu, Jonathan J. Rios, Chenchen Yang, Crystal N. Marconett, Suhaida A. Selamat, Ite A. Laird-Offringa, Ayumu Taguchi, Samir Hanash, David Shames, Xiaotu Ma, Michael Q. Zhang, Wan L. Lam, Adi Gazdar

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

INTRODUCTION:: CDKN2A (p16) inactivation is common in lung cancer and occurs via homozygous deletions, methylation of promoter region, or point mutations. Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. METHODS:: We determined all three p16 inactivation mechanisms with the use of multiple methodologies for genomic status, methylation, RNA, and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary non-small-cell lung carcinoma. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. RESULTS:: p16 inactivation was the major mechanism of RB pathway perturbation in non-small-cell lung carcinoma, with homozygous deletion being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS, and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. CONCLUSION:: Our results confirm that all the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status.

Original languageEnglish (US)
Pages (from-to)1378-1388
Number of pages11
JournalJournal of Thoracic Oncology
Volume8
Issue number11
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

Fingerprint

Non-Small Cell Lung Carcinoma
Smoke
Methylation
Smoking
Mutation
Tumor Cell Line
Point Mutation
Meta-Analysis
Genetic Promoter Regions
Lung Neoplasms
Proteins
RNA
Messenger RNA
Genes

Keywords

  • Adenocarcinoma
  • CDKN2A
  • Homozygous deletion
  • Inactivation
  • Lung cancer
  • Meta-analysis
  • Methylation
  • p16

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small-cell lung cancer. / Tam, Kit; Zhang, Wei; Soh, Junichi; Stastny, Victor; Chen, Min; Sun, Han; Thu, Kelsie; Rios, Jonathan J.; Yang, Chenchen; Marconett, Crystal N.; Selamat, Suhaida A.; Laird-Offringa, Ite A.; Taguchi, Ayumu; Hanash, Samir; Shames, David; Ma, Xiaotu; Zhang, Michael Q.; Lam, Wan L.; Gazdar, Adi.

In: Journal of Thoracic Oncology, Vol. 8, No. 11, 01.01.2013, p. 1378-1388.

Research output: Contribution to journalArticle

Tam, K, Zhang, W, Soh, J, Stastny, V, Chen, M, Sun, H, Thu, K, Rios, JJ, Yang, C, Marconett, CN, Selamat, SA, Laird-Offringa, IA, Taguchi, A, Hanash, S, Shames, D, Ma, X, Zhang, MQ, Lam, WL & Gazdar, A 2013, 'CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small-cell lung cancer', Journal of Thoracic Oncology, vol. 8, no. 11, pp. 1378-1388. https://doi.org/10.1097/JTO.0b013e3182a46c0c
Tam, Kit ; Zhang, Wei ; Soh, Junichi ; Stastny, Victor ; Chen, Min ; Sun, Han ; Thu, Kelsie ; Rios, Jonathan J. ; Yang, Chenchen ; Marconett, Crystal N. ; Selamat, Suhaida A. ; Laird-Offringa, Ite A. ; Taguchi, Ayumu ; Hanash, Samir ; Shames, David ; Ma, Xiaotu ; Zhang, Michael Q. ; Lam, Wan L. ; Gazdar, Adi. / CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small-cell lung cancer. In: Journal of Thoracic Oncology. 2013 ; Vol. 8, No. 11. pp. 1378-1388.
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abstract = "INTRODUCTION:: CDKN2A (p16) inactivation is common in lung cancer and occurs via homozygous deletions, methylation of promoter region, or point mutations. Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. METHODS:: We determined all three p16 inactivation mechanisms with the use of multiple methodologies for genomic status, methylation, RNA, and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary non-small-cell lung carcinoma. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. RESULTS:: p16 inactivation was the major mechanism of RB pathway perturbation in non-small-cell lung carcinoma, with homozygous deletion being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS, and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. CONCLUSION:: Our results confirm that all the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status.",
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T1 - CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small-cell lung cancer

AU - Tam, Kit

AU - Zhang, Wei

AU - Soh, Junichi

AU - Stastny, Victor

AU - Chen, Min

AU - Sun, Han

AU - Thu, Kelsie

AU - Rios, Jonathan J.

AU - Yang, Chenchen

AU - Marconett, Crystal N.

AU - Selamat, Suhaida A.

AU - Laird-Offringa, Ite A.

AU - Taguchi, Ayumu

AU - Hanash, Samir

AU - Shames, David

AU - Ma, Xiaotu

AU - Zhang, Michael Q.

AU - Lam, Wan L.

AU - Gazdar, Adi

PY - 2013/1/1

Y1 - 2013/1/1

N2 - INTRODUCTION:: CDKN2A (p16) inactivation is common in lung cancer and occurs via homozygous deletions, methylation of promoter region, or point mutations. Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. METHODS:: We determined all three p16 inactivation mechanisms with the use of multiple methodologies for genomic status, methylation, RNA, and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary non-small-cell lung carcinoma. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. RESULTS:: p16 inactivation was the major mechanism of RB pathway perturbation in non-small-cell lung carcinoma, with homozygous deletion being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS, and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. CONCLUSION:: Our results confirm that all the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status.

AB - INTRODUCTION:: CDKN2A (p16) inactivation is common in lung cancer and occurs via homozygous deletions, methylation of promoter region, or point mutations. Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. METHODS:: We determined all three p16 inactivation mechanisms with the use of multiple methodologies for genomic status, methylation, RNA, and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary non-small-cell lung carcinoma. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. RESULTS:: p16 inactivation was the major mechanism of RB pathway perturbation in non-small-cell lung carcinoma, with homozygous deletion being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS, and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. CONCLUSION:: Our results confirm that all the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status.

KW - Adenocarcinoma

KW - CDKN2A

KW - Homozygous deletion

KW - Inactivation

KW - Lung cancer

KW - Meta-analysis

KW - Methylation

KW - p16

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