Skip to main content
Log in

Frequent 3p21 allelic loss and methylation-associated RASSF1A inactivation in non-small cell lung cancer and its clinical implication

  • Published:
Wuhan University Journal of Natural Sciences

Abstract

A total of 110 primary NSCLCs (non-small cell lung cancers) were recruited in this study to characterize the pattern of 3p21 LOH together with the RASSF1A methylation status and their clinical implication. 3p21 LOH by 8 microsatellite markers, RASSF1A methylation status by methylation-specific PCR (MSPCR) as well as bisulfite genomic sequencing (BGS), and RASSF1A expression level by real-time quantitative PCR was performed. 3p21 LOH is frequent in NSCLC with a mean frequency of (41.2±3.7)%. Significant associations between 3p21 LOH and gender, smoking history, histological type, and tumor size were observed. Cases with LOH have a slightly lower RASSF1A expression than cases without LOH but not statistically significant. Comparison of RASSF1A methylation that resulted from the three analyses shows significant correlations from one another. Higher frequency of methylation was observed in larger tumors and in smokers compared with smaller tumors and non-smokers, respectively. A significant correlation was also observed in extent between methylation and RASSF1A expression, illustrating that epigenetic mechanism could affect gene expression. The significant clinicopathological relations of 3p21 LOH may be of great use for both early detection and therapeutic interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Chorostowska-Wynimko J, Szpechcinski A. The Impact of Genetic Markers on the Diagnosis of Lung Cancer: A Current Perspective[J]. J Thorac Oncol, 2007, 2(11): 1044–1051.

    Article  Google Scholar 

  2. Roche J, Boldog F, Robinson M, et al. Distinct 3p21.3 Deletions in Lung Cancer and Identification of a New Human Semaphorin[J]. Oncogene, 1996, 12(16): 1289–1297.

    Google Scholar 

  3. Sekido Y, Ahmadian M, Wistuba I I, et al. Cloning of a Breast Cancer Homozygous Deletion Junction Narrows the Region of Search for a 3p21.3 Tumor Suppressor Gene[J]. Oncogene, 1998, 16(24): 3151–3157.

    Article  Google Scholar 

  4. Lerman M I, Minna J D. The 630-kb Lung Cancer Homozygous Deletion Region on Human Chromosome 3p21.3: Identification and Evaluation of the Resident Candidate Tumor Suppressor Genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium[J]. Cancer Res, 2000, 60(21): 6116–6133.

    Google Scholar 

  5. Avruch J, Xavier R, Bardeesy N, et al. Rassf Family of Tumor Suppressor Polypeptides[J]. J Biol Chem, 2009, 284(17): 11001–11005.

    Article  Google Scholar 

  6. van der Weyden L, Adams D J. The Ras-association Domain Family (RASSF) Members and Their Role in Human Tumourigenesis[J]. Biochim Biophys Acta, 2007, 1776(1): 58–85.

    Google Scholar 

  7. Shivakumar L, Minna J, Sakamaki T, et al. The RASSF1A Tumor Suppressor Blocks Cell Cycle Progression and Inhibits Cyclin D1 Accumulation[J]. Mol Cell Biol, 2002, 22(12): 4309–4018.

    Article  Google Scholar 

  8. Burbee D G, Forgacs E, Zöchbauer-Müller S, et al. Epigenetic Inactivation of RASSF1A in Lung and Breast Cancers and Malignant Phenotype Suppression[J]. J Natl Cancer Inst, 2001, 93(9): 691–699.

    Article  Google Scholar 

  9. Agathanggelou A, Cooper W N, Latif F. Role of the Ras-Association Domain Family 1 Tumor Suppressor Gene in Human Cancers[J]. Cancer Res, 2005, 65(9): 3497–3508.

    Article  Google Scholar 

  10. Tomizawa Y, Kohno T, Kondo H, et al. Clinicopathological Significance of Epigenetic Inactivation of RASSF1A at 3p21.3 in Stage I Lung Adenocarcinoma[J]. Clin Cancer Res, 2002, 8(7): 2362–2368.

    Google Scholar 

  11. Endoh H, Yatabe Y, Shimizu S, et al. RASSF1A Gene Inactivation in Non-Small Cell Lung Cancer and Its Clinical Implication[J]. Int J Cancer, 2003. 106(1): 45–51.

    Article  Google Scholar 

  12. Honorio S, Agathanggelou A, Schuermann M, et al. Detection of RASSF1A Aberrant Promoter Hypermethylation in Sputum from Chronic Smokers and Ductal Carcinoma in Situ from Breast Cancer Patients[J]. Oncogene, 2003, 22(1): 147–150.

    Article  Google Scholar 

  13. Zhu H, Lam D C, Han K C, et al. High Resolution Analysis of Genomic Aberrations by Metaphase and Array Comparative Genomic Hybridization Identifies Candidate Tumour Genes in Lung Cancer Cell Lines[J]. Cancer Lett, 2007, 245(1–2): 303–314.

    Article  Google Scholar 

  14. Wistuba II, Behrens C, Virmani A K, et al. High Resolution Chromosome 3p Allelotyping of Human Lung Cancer and Preneoplastic/Preinvasive Bronchial Epithelium Reveals Multiple, Discontinuous Sites of 3p Allele Loss and ThreeRegions of Frequent Breakpoints[J]. Cancer Res, 2000, 60(7): 1949–1960.

    Google Scholar 

  15. Oh J J, Koegel A K, Phan D T, et al. The Two Single Nucleotide Polymorphisms in the H37/RBM5 Tumour Suppressor Gene at 3p21.3 Correlated with Different Subtypes of Non-Small Cell Lung Cancers[J]. Lung Cancer, 2007, 58(1): 7–14.

    Article  Google Scholar 

  16. Marsit CJ, Hasegawa M, Hirao T, et al. Loss of Heterozygosity of Chromosome 3p21 Is Associated with Mutant TP53 and Better Patient Survival in Non-Small-Cell Lung Cancer[J]. Cancer Res, 2004, 64(23): 8702–8707.

    Article  Google Scholar 

  17. Ito M, Ito G, Kondo M, et al. Frequent Inactivation of RASSF1A, BLU, and SEMA3B on 3p21.3 by Promoter Hypermethylation and Allele Loss in Non-Small Cell Lung Cancer[J]. Cancer Lett, 2005, 225(1): 131–139.

    Article  Google Scholar 

  18. Hirao T, Nelson H H, Ashok T D, et al. Tobacco Smoke-Induced DNA Damage and an Early Age of Smoking Iinitiation Induce Chromosome Loss at 3p21 in Lung Cancer[J]. Cancer Res, 2001, 61(2): 612–615.

    Google Scholar 

  19. Mitsudomi T, Oyama T, Nishida K, et al. Loss of Heterozygosity at 3p in Non-Small Cell Lung Cancer and Its Prognostic Implication[J]. Clin Cancer Res, 1996; 2(7): 1185–1189.

    Google Scholar 

  20. Iijima H, Tomizawa Y, Dobashi K, et al. Allelic Losses on Chromosome 3p are Accumulated in Relation to Morphological Changes of Lung Adenocarcinoma[J]. Br J Cancer, 2004, 91(6): 1143–1148.

    Google Scholar 

  21. Dammann R, Li C, Yoon J H, et al. Epigenetic Inactivation of a RAS Association Domain Family Protein from the Lung Tumour Suppressor Locus 3p21.3[J]. Nat Genet, 2000, 25(3): 315–319.

    Article  Google Scholar 

  22. Agathanggelou A, Honorio S, Macartney D P, et al. Methylation Associated Inactivation of RASSF1A from Region 3p21.3 in Lung, Breast and Ovarian Tumours[J]. Oncogene, 2001, 20(12): 1509–1518.

    Article  Google Scholar 

  23. Toyooka S, Maruyama R, Toyooka K O, et al. Smoke Exposure, Histologic Type and Geography-Related Differences in the Methylation Profiles of Non-Small Cell Lung Cancer[J]. Int J Cancer, 2003, 103(2): 153–160.

    Article  Google Scholar 

  24. Yanagawa N, Tamura G, Oizumi H, et al. Promoter Hypermethylation of Tumor Suppressor and Tumor-Related Genes in Non-Small Cell Lung Cancers[J]. Cancer Sci, 2003, 94(7): 589–592.

    Article  Google Scholar 

  25. Marsit C J, Kim D H, Liu M, et al. Hypermethylation of RASSF1A and BLU Tumor Suppressor Genes in Non-Small Cell Lung Cancer: Implications for Tobacco Smoking during Adolescence[J]. Int J Cancer, 2005, 114(2): 219–223.

    Article  Google Scholar 

  26. Jones P A, Laird P W. Cancer Epigenetics Comes of Age[J]. Nat Genet, 1999, 21(2): 163–167.

    Article  Google Scholar 

  27. Baylin S B. Mechanisms Underlying Epigenetically Mediated Gene Silencing in Cancer[J]. Semin Cancer Biol, 2002, 12(5): 331–337.

    Article  Google Scholar 

  28. Cameron E E, Baylin S B, Herman J G. p15(INK4B) CpG Island Methylation in Primary Acute Leukemia is Heterogeneous and Suggests Density as a Critical Factor for Transcriptional Silencing[J]. Blood, 1999, 94(7): 2445–2451.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hong Zhu.

Additional information

Foundation item: Supported by grants from the Research Grants Council of the Hong Kong Special Administrative Region (HKU7310/01M, 7486/03M, 7468/04)

Biography: ZHU Hong (1970–), female, attending doctor, Ph. D., research direction: molecular genetics of lung cancer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhu, H., Wong, M.P. Frequent 3p21 allelic loss and methylation-associated RASSF1A inactivation in non-small cell lung cancer and its clinical implication. Wuhan Univ. J. Nat. Sci. 14, 457–464 (2009). https://doi.org/10.1007/s11859-009-0517-x

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11859-009-0517-x

Key words

CLC number

Navigation