Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome
- 192 Downloads
Cyclin D1 is one of the major cellular oncogenes, overexpressed in number of human cancers, including non-small cell lung carcinoma (NSCLC). However, it does not exert tumorigenic activity by itself, but rather cooperates with other altered oncogenes and tumor suppressors. Therefore, in the present study, we have examined mutual role of cyclin D1, KRAS, and PTEN alterations in the pathogenesis of NSCLC and their potential to serve as multiple molecular markers for this disease. CCND1 gene amplification and gene expression were analyzed in relation to mutational status of KRAS gene as well as to PTEN alterations (loss of heterozygosity and promoter hypermethylation) in NSCLC patient samples. Moreover, the effect of these co-alterations on patient survival was examined. Amplified CCND1 gene was exclusively associated with increased gene expression. Statistical analyses also revealed significant association between CCND1 overexpression and KRAS mutations in the whole group and in the groups of patients with adenocarcinoma, grade 1/2, and stage I/II. In addition, CCND1 overexpression was significantly related to PTEN promoter hypermethylation in the whole group and in the group of patients with squamous cell carcinoma and lymph node invasion. These joint alterations also significantly shortened patients’ survival and were shown to be an independent factor for adverse prognosis. Overall results point that cyclin D1 expression cooperates with KRAS and PTEN alterations in pathogenesis of NSCLC, and they could serve as potential multiple molecular markers for specific subgroups of NSCLC patients as well as prognostic markers for this type of cancer.
KeywordsCCND1 KRAS PTEN Non-small cell lung carcinoma
This study was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (grant No III41031).
Conflicts of interest
- 13.Sunpaweravong P, Sunpaweravong S, Puttawibul P, Mitarnun W, Zeng C, Baron AE, et al. Epidermal growth factor receptor and cyclin D1 are independently amplified and overexpressed in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2005;131(2):111–9. doi: 10.1007/s00432-004-0610-7.CrossRefPubMedGoogle Scholar
- 15.Tanic N, Milinkovic V, Dramicanin T, Nedeljkovic M, Stankovic T, Milovanovic Z et al. Amplification of Cycline D1, C-Myc and Egfr Oncogenes in Tumour Samples of Breast Cancer Patients. J Med Biochem. 2013;32(4). doi: 10.2478/jomb-2014-0005.
- 17.Sambrook J. Purification of Nucleic Acids. In: Nolan C, editor. Molecular cloning: a laboratory manual. secondth ed. Cold Spring Harbour: Cold Spring Harbor: Laboratory Press; 1989. p. E.3–4.Google Scholar
- 21.NicAmhlaoibh R, Heenan M, Cleary I, Touhey S, O'Loughlin C, Daly C, et al. Altered expression of mRNAs for apoptosis-modulating proteins in a low level multidrug resistant variant of a human lung carcinoma cell line that also expresses mdr1 mRNA. Int J Cancer J Int du Cancer. 1999;82(3):368–76.CrossRefGoogle Scholar
- 23.COSMIC: Catalogue of Somatic Mutations in Cancer, http://cancer.sanger.ac.uk/cosmic
- 35.Sartori G, Cavazza A, Bertolini F, Longo L, Marchioni A, Costantini M, et al. A subset of lung adenocarcinomas and atypical adenomatous hyperplasia-associated foci are genotypically related: an EGFR, HER2, and K-ras mutational analysis. Am J Clin Pathol. 2008;129(2):202–10. doi: 10.1309/THU13F3JRJVWLM30.CrossRefPubMedGoogle Scholar
- 42.Kurose K, Zhou XP, Araki T, Cannistra SA, Maher ER, Eng C. Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas. Am J Pathol. 2001;158(6):2097–106. doi: 10.1016/S0002-9440(10)64681-0.CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Marsit CJ, Zheng S, Aldape K, Hinds PW, Nelson HH, Wiencke JK, et al. PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol. 2005;36(7):768–76. doi: 10.1016/j.humpath.2005.05.006.CrossRefPubMedGoogle Scholar