Genome-wide combination profiling of DNA copy number and methylation for deciphering biomarkers in non-small cell lung cancer patients

Son, Ji Woong; Jeong, Kang Jin; Jean, Woo Sean; Park, Soon Young; Jheon, Sanghoon; Cho, Hyun Min; Park, Chang Gyo; Lee, Hoi Young; Kang, Jaeku

doi:10.1016/j.canlet.2011.06.021

Cited by 51 publications

(39 citation statements)

References 41 publications

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“…Our data are consistent with HOXA9 acting as a tumor suppressor in oral cancer. Methylation of HOXA9 has been reported previously in oral cavity cancer [6], and methylation and loss of expression of HOXA9 reported in breast [4,7,8], lung [9], ovarian [10] and bladder cancer [11], whereas HOXA9 is well known to act as an oncogene in leukemia [5]. The tumor suppressor function of HOXA9 has been extensively investigated in breast cancer where it has been shown that HOXA9 directly regulates BRCA1 [4] and a number of other genes involved in invasion, growth and metastasis [7].…”

Section: Discussionmentioning

confidence: 98%

Investigation of HOXA9 promoter methylation as a biomarker to distinguish oral cancer patients at low risk of neck metastasis

et al. 2014

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BackgroundMetastasis to the cervical (neck) lymph nodes is one of the most significant clinical factors responsible for death from oral squamous cell carcinoma (SCC). Therefore, the lymph nodes are frequently removed when the tumor is excised (neck dissection), even though the majority of patients will not benefit from the extra surgery. Two subtypes of oral SCC distinguished by the presence of tumor genomic aberrations +3q, -8p, +8q and/or +20 differ in risk for metastasis – high for the 3q8pq20 subtype, harboring one or more of the aberrations and low for the non-3q8pq20 subtype, lacking these alterations. A prior analysis of the literature suggested genes differentially methylated in the two subtypes. Therefore, the goal of this study was to further investigate the methylation status of candidate biomarkers of the non-3q8pq20 subtype, and evaluate their utility for identifying patients at low risk for metastasis.MethodsMethylation status of genes in a cohort of 52 oral SCC patients with at least five year follow up was determined by pyrosequencing. Gene expression levels were determined by quantitative RT-PCR. Growth following re-expression of HOXA9 in cultured oral SCC cells was assessed by proliferation and colony formation assays.ResultsA pilot study evaluating methylation levels of HOXA9, MT1A and HOXA11 promoters in DNA from 12 tumors (six each of the 3q8pq20 and non-3q8pq20 subtypes) revealed that only HOXA9 was differentially methylated. Significant differences in methylation levels of HOXA9 were observed amongst the 52 oral SCCs with respect to genomic subtype and nodal status (p = 0.014, and p = 0.024, respectively, Wilcoxon rank sum test). High levels of HOXA9 methylation and low levels of expression in oral SCC cell lines were observed compared to HaCaT, a non-tumorigenic keratinocyte cell line. Re-expression of HOXA9 in the SCC4 oral cancer cell line resulted in diminished proliferation and colony formation.ConclusionsHOXA9 methylation is frequent in oral cancers and levels are higher in tumors with greater risk of metastasis. Expression of HOXA9 is low in cells with high levels of methylation and reduced expression appears to confer a growth advantage.

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Section: Discussionmentioning

confidence: 98%

Investigation of HOXA9 promoter methylation as a biomarker to distinguish oral cancer patients at low risk of neck metastasis

et al. 2014

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“…A surfeit of these genomic aberrations has been discovered in tumour cells/tissues and includes base-pair substitutions/additions/deletions and chromosomal-rearrangements leading to copy number gain or losses [78][79][80][81][82][83]. Next-generation sequencing technologies have emerged as superior high-throughput genome characterization techniques to account for varied genetic differences, subtle or extensive, in tumour-normal sample pairs.…”

Section: Genomic Aberration Of Frk In Cancermentioning

confidence: 99%

Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology

Goel

Lukong

2016

Cancer Metastasis Rev

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The non-receptor tyrosine kinase Fyn-related kinase (FRK) is a member of the BRK family kinases (BFKs) and is distantly related to the Src family kinases (SFKs). FRK was first discovered in 1993, and studies pursued thereafter attributed a potential tumour-suppressive function to the enzyme. In recent years, however, further functional characterization of the tyrosine kinase in diverse cancer types suggests that FRK may potentially play an oncogenic role as well. Specifically, while ectopic expression of FRK suppresses cell proliferation and migration in breast and brain cancers, knockdown or catalytic inhibition of FRK suppresses these cellular processes in pancreatic and liver cancer. Such functional paradox is therefore evidently exhibited in a tissue-specific context. This review sheds light on the recent developments emerged from investigations on FRK which include: (a) a review of the expression pattern of the protein in mammalian cells/tissues, (b) underlying genomic perturbations and (c) a mechanistic function of the enzyme across different cellular environments. Given its functional heterogeneity observed across different cancers, we also discuss the therapeutic significance of FRK.

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“…Recently, more advanced platforms have been delivered to the market, such as the 450K beadchip array from Illumina. In these 4 years, several genome-wide analyses have been carried using non-small/small cell lung cancer and normal lung tissues identifying new aberrant epigenetic changes with potential diagnostic value (Nelson et al 2012;Heller et al 2013;Morán et al 2012;Son et al 2011). Interestingly, a study comparing 169 adenocarcinomas and 72 squamous cell carcinomas revealed divergent genomic and epigenomic landscapes in non-small lung cancer subtypes (Lockwood et al 2012).…”

Section: Diagnosismentioning

confidence: 97%

Epigenomic Biomarkers for the Advance of Personalized Medicine

Méndez‐González

Sandoval

2015

Translational Bioinformatics

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Epigenetic factors (DNA methylation, histone modifications, or ncRNAs) are involved in gene expression regulation. Thus, determining abnormal epigenetic changes is a suitable approach to extract meaningful information about human diseases. An altered pattern of epigenetic modifications has been firstly defined as a hallmark for cancer, although it is also a key element to many common human diseases, such as cardiovascular, metabolic, and neurological pathologies. During the last decade, the advent of genome-scale analysis techniques applied to epigenetics has provided a massive amount of data, enabling an important advance in the molecular mechanisms underlying disease initiation, progression, and expansion. Disease-specific epigenomic signatures, mainly based on DNA methylation analysis, have been studied for several clinical purposes including prognostics and diagnostics, as well as disease-specific chemotherapy response. Using noninvasive specimens, epigenetic profiling holds the promise of being of clinical value in the management of patients, even at the early stages of disease. Additionally, epigenetic marks have also been catalogued as targets for pharmacological drugs. The upgrade of epigenetic research to epigenomics together with other -omics would tackle the many unanswered questions in the field, paving the path to achieve a more precise personalized medicine.

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Genome-wide combination profiling of DNA copy number and methylation for deciphering biomarkers in non-small cell lung cancer patients

Cited by 51 publications

References 41 publications

Investigation of HOXA9 promoter methylation as a biomarker to distinguish oral cancer patients at low risk of neck metastasis

Investigation of HOXA9 promoter methylation as a biomarker to distinguish oral cancer patients at low risk of neck metastasis

Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology

Epigenomic Biomarkers for the Advance of Personalized Medicine

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