Epigenetic changes in non-small cell lung cancer

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Epigenetic changes have been shown to play an important role in carcinogenetic processes. Out of these changes, the most studied one is tumor growth suppressor gene promoter hypermethylation that is one of the key mechanisms for increasing or decreasing gene expression in non-small cell lung cancer (NSCLC). The changes occurring in the tumor stroma and apparently normal tissues surrounding the tumor, the so-called cancerization fields, have a profound effect on tumor formation and progression. Epigenetic changes in the tumor and surrounding tissue were analyzed to identify these in different histological types of NSCLC, to estimate the extent of the study changes in the tumor-adjacent tissue and to reveal their possible associations with the clinical and morphological parameters of patients. Tumor and adjacent apparently normal tissue samples from 110 patients diagnosed as having NSCLC served as the material for investigation. The promoter hypermethylation of the RASSF1A (3p21.3), FHIT (3p14.2), DAPK1 (9q21.33), CDH1 (16q22.1), CD44 (11p13), TIMP3 (22q12.3), and MGMT (10q26.3) genes was analyzed using methylation-sensitive restriction polymerase chain reaction and bisulfite sequencing. Epigenetic changes were found in one of the study genes in 95% of the patients with NSCLC. In the latter, the rate of tumor epigenetic changes was 70% for the RASSF1A gene, 52% for the FHIT gene, and 17% for the DAPK1 gene. Statistically significant associations were found between the promoter hypermethylation of the CDH1 and CD44 genes and squamous cell cancer and between the concurrent promoter hypermethylation of the RASSF1A and FHIT genes and late disease stages (III-IV) with regional lymph node metastases. The epigenetic changes in the DAPK1 gene were shown to be associated with tumor spread. The epigenetic changes found in the promoters of the RASSF1A and FHIT genes may be regarded as markers for unfavorable prognosis in the disease and the promoter hypermethylation of the DAPK1 gene may be considered as a metastasis-associated marker.

Keywords:

non-small cell lung cancer

epigenetic changes

Authors:

Shikeeva A.A.

FGBU "Moskovskiĭ nauchno-issledovatel'skiĭ onkologicheskiĭ institut im. P.A. Gertsena" Minzdrava Rossii

Kekeeva T.V.

FGBU "Moskovskiĭ nauchno-issledovatel'skiĭ onkologicheskiĭ institut im. P.A. Gertsena" Minzdrava Rossii

Zavalishina L.É.

FGBU "Moskovskiĭ nauchno-issledovatel'skiĭ onkologicheskiĭ institut im. P.A. Gertsena" Minzdravsotsrazvitiia Rossii

Andreeva Yu.Yu.

Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia

SPIN RSCI: 6504-2551
Scopus AuthorID: 8656328100
ORCID: 0000-0003-4749-6608

Frank G.A.

Moskovskiĭ nauchno-issledovatel'skiĭ onkologicheskiĭ institut im. P.A. Gertsena Rosmedtekhnologiĭ, Moskva

ORCID: 0000-0002-3719-5388

List of references:

Van Den Broeck A., Ozenne P., Eymin B., Gazzeri S. Lung cancer. A modified epigenome. Cell Adhes. Migration. 2009; 4 (1): 107-13.
Zaletaev D.V., Pal'tsev M.A., red. Sistemy geneticheskikh i epigeneticheskikh markerov v diagnostike onkologicheskikh zabolevanii. M.: Meditsina; 2009. 384 s.
Heller G., Zielinski C.C., Zochbauer-Muller S. Lung cancer: from single-gene methylation to methylome profiling. Cancer Metastas. Rev. 2010; 29: 95-107.
Leonhardt H., Cardoso M.C. DNA methylation, nuclear structure, gene expression and cancer. J. Cell Biochem. 2000; Suppl. 35: 78-83.
Baylin S.B., Herman J.G. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet. 2000; 16: 168-74.
Wen J., Fu J., Zhang W., Guo M. Genetic and epigenetic changes in lung carcinoma and their clinical implications Mod. Pathol. 2011; 24: 932-43.
Ji M., Zhang Y., Shi B., Hou P. Association of promoter methylation with histologic type and pleural indentation in non-small cell lung cancer (NSCLC). Diagn. Pathol. 2011; 6: 48.
Begum S., Brait M., Dasgupta S., Ostrow K.L., Zahurak M., Carvalho A.L. et al. An epigenetic marker panel for detection of lung cancer using cell-free serum DNA. Clin. Cancer Res. 2011; 17 (13): 4494-503.
Slaughter D.P., Southwick H.W., Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric ori-gin. Cancer. 1953; 6 (5): 963-8.
Braakhuis B.J., Tabor M.P., Kummer J.A., Leemans C.R., Brakenhoff R.H. A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res. 2003, 63: 1727-30.
Guo M., House M.G., Hooker C., Han Y., Heath E., Gabrielson E. et al. Promoter hypermethylation of resected bronchial margins: a field defect of changes? Clin. Cancer Res. 2004; 10: 5131-513.
Nakajima T., Oda I., Gotoda T., Hamanaka H., Eguchi T., Yokoi C., Saito D. Metachronous gastric cancers after endoscopic resection: how effective is annual endoscopic surveillance? Gastric Cancer. 2006; 9: 93-8.
Nakajima T., Maekita T., Oda I., Gotoda T., Yamamoto S., Umemura S. et al. Higher methylation levels in gastric mucosae significantly correlate with higher risk of gastric cancers. Cancer Epidemiol. Biomarkers Prev. 2006; 15: 2317-21.
Partridge M., Pateromichelakis S., Phillips E., Emilion G.G., A'Hern R.P., Langdon J.D. A case-control study confirms that microsatellite assay can identify patients at risk of developing oral squamous cell carcinoma within a field of cancerization. Cancer Res. 60: 3893-8.
Wistuba I.I., Gazdar A.F. Lung cancer preneoplasia. Annu. Rev. Pathol. 2006; 1: 331-48.
Wistuba I.I., Behrens C., Virmani A.K., Mele G., Milchgrub S., Girard L. 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 three regions of frequent breakpoints. Cancer Res. 2000; 60: 1949-60.
Miyazaki M., Ohno S., Futatsugi M., Saeki H., Ohga T., Watanabe M. The relation of alcohol consumption and cigarette smoking to the multiple occurrence of esophageal dysplasia and squamous cell carcinoma. Surgery. 2002; 131: 7-13.
Hafner C., Knuechel R., Stoehr R., Hartmann A. Clonality of multifocal urothelial carcinomas: 10 years of molecular genetic studies. Int. J. Cancer. 2002; 101: 1-6.
Eads C.A., Lord R.V., Kurumboor S.K., Wickramasinghe K., Skinner M.L., Long T.I. et al. Fields of aberrant CpG island hypermethylation in Barrett's esophagus and associated adenocarcinoma. Cancer Res. 2000; 60: 5021-6.
Issa J.P., Ahuja N., Toyota M., Bronner M.P., Brentnall T.A. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res. 2001; 61: 3573-7.
Kondo Y., Kanai Y., Sakamoto M., Mizokami M., Ueda R., Hirohashi S. Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis - a comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma. Hepatology. 2000; 32: 970-9.
Arai E., Kanai Y., Ushijima S., Fujimoto H., Mukai K., Hirohashi S. Regional DNA hypermethylation and DNA methyltransferase (DNMT) 1 protein overexpression in both renal tumors and corresponding nontumorous renal tissues. Int. J. Cancer. 2006; 119: 288-96.
Shen L., Kondo Y., Rosner G.L., Xiao L., Hernandez N.S., Vilaythong J. et al. MGMT promoter methylation and field defect in sporadic colorectal cancer. J. Natl. Cancer Inst. 2005; 97: 1330-8.
Yan P.S., Venkataramu C., Ibrahim A., Liu J.C., Shen R.Z., Diaz N.M. et al. Mapping geographic zones of cancer risk with epigenetic biomarkers in normal breast tissue. Clin. Cancer Res. 2006; 12: 6626-36.
Shikeeva A.A., Kekeeva T.V., Zavalishina L.E., Andreeva Yu.Yu., Frank G.A. Analiz molekulyarno-geneticheskikh izmenenii dlya differentsial'noi diagnostiki leiomiosarkom i proliferiruyushchikh leiomiom matki. Molekulyarnaya meditsina. 2011; 6: 38-43.
Strel'nikov V.V., Malysheva A.S., Zemlyakova V.V., Kuznetsova E.B., Alekseeva E.A., Smolin A.V. i dr. Deletsii oblasti raspolozheniya gena MGMT na khromosome 10q26.3 v gliomakh. Molekulyarnaya meditsina. 2011; 2: 28-31.
Alekseeva E.A., Gorbacheva Yu.V., Babenko O.V., Zemlyakova V.V., Kuznetsova E.B., Smolin A.V. i dr. Molekulyarno-geneticheskaya differentsial'naya diagnostika opukholei golovnogo mozga. Meditsinskaya genetika. 2012; 11 (1): 10-4.
Alekseeva E.A., Shubina M.V., Gorbacheva Yu.V., Babenko O.V., Zemlyakova V.V., Kuznetsova E.B. i dr. Molekulyarno-geneticheskaya diagnostika v targetnoi terapii opukholei golovnogo mozga. Meditsinskaya genetika. 2012; 11 (2): 3-10.
Maruyama R., Sugio K., Yoshino I., Maehara Y., Gazdar A.F. Hypermethylation of FHIT as a prognostic marker in non-small cell lung carcinoma. Cancer. 2004; 100: 1472-7.
Gu J., Berman D., Lu C., Wistuba I.I., Roth J.A., Frazier M. et al. Aberrant promoter methylation profile and association with survival in patients with non-small cell lung cancer. Clin. Cancer Res. 2006; 12: 7329-38.
Shikeeva A.A., Kekeeva T.V., Zavalishina L.E., Andreeva Yu.Yu., Frank G.A. Allel'nye narusheniya u patsientov s nemelkokletochnym rakom legkogo. Arkhiv patologii. 2013; 75 (2): 3-8.

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