Genome-wide combination profiling of copy number and methylation offers an approach for deciphering misregulation and development in cancer cells

Park, Jung Jun; Kang, Jaeku; Hong, Su Hyung; Ryu, Eun Sook; Kim, Jong‐Il; Lee, Jong Ho; Seo, Jong-Soo

doi:10.1016/j.gene.2007.10.011

Cited by 8 publications

(5 citation statements)

References 47 publications

(57 reference statements)

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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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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 need for combined high-resolution profiling of DNA copy number and methylation profiling is becoming recognized, particularly as pharmacologic targeting of the epigenome has gained momentum, and methods to simultaneously investigate both types of alterations are emerging [24], [25], [26]. In addition, recent investigations in gliomas [21] and cancer cell lines [27], [28] using combinatorial high-throughput methods have elucidated individual genes that are differentially regulated through these mechanisms; however, the global relationships between epigenetic and copy number profiles in human tumors remain poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

Genetic and Epigenetic Somatic Alterations in Head and Neck Squamous Cell Carcinomas Are Globally Coordinated but Not Locally Targeted

et al. 2010

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BackgroundSolid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Little work has been done that simultaneously examines the spectrum of both types of changes in human tumors on a genome-wide scale and results so far have been limited and mixed. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC.Methodology/Principal FindingsWe have extended a prior analysis of 1,413 cancer-associated loci for epigenetic changes in HNSCC by integrating DNA copy number alterations, measured at 500,000 polymorphic loci, in a case series of 19 primary HNSCC tumors. We have previously demonstrated that local copy number does not bias methylation measurements in this array platform. Importantly, we found that the global pattern of copy number alterations in these tumors was significantly associated with tumor methylation profiles (p<0.002). However at the local level, gene promoter regions did not exhibit a correlation between copy number and methylation (lowest q = 0.3), and the spectrum of genes affected by each type of alteration was unique.Conclusion/SignificanceThis work, using a novel and robust statistical approach demonstrates that, although a “second hit” mechanism is not likely the predominant mode of action for epigenetic dysregulation in cancer, the patterns of methylation events are associated with the patterns of allele loss. Our work further highlights the utility of integrative genomics approaches in exploring the driving somatic alterations in solid tumors.

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“…40 Possible copy number changes of the region were also observed from cancer cell line data. 41 Regions 1p21.1 and 10q21.1 have also been reported repeatedly for potential association with breast cancer. Chromosome arm 1p was suggested to contain multiple tumor suppressor genes.…”

Section: Discussionmentioning

confidence: 83%

A Single-Array-Based Method for Detecting Copy Number Variants Using Affymetrix High Density SNP Arrays and its Application to Breast Cancer

Wen

2014

Cancer Inform

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Cumulative evidence has shown that structural variations, due to insertions, deletions, and inversions of DNA, may contribute considerably to the development of complex human diseases, such as breast cancer. High-throughput genotyping technologies, such as Affymetrix high density single-nucleotide polymorphism (SNP) arrays, have produced large amounts of genetic data for genome-wide SNP genotype calling and copy number estimation. Meanwhile, there is a great need for accurate and efficient statistical methods to detect copy number variants. In this article, we introduce a hidden-Markov-model (HMM)-based method, referred to as the PICR-CNV, for copy number inference. The proposed method first estimates copy number abundance for each single SNP on a single array based on the raw fluorescence values, and then standardizes the estimated copy number abundance to achieve equal footing among multiple arrays. This method requires no between-array normalization, and thus, maintains data integrity and independence of samples among individual subjects. In addition to our efforts to apply new statistical technology to raw fluorescence values, the HMM has been applied to the standardized copy number abundance in order to reduce experimental noise. Through simulations, we show our refined method is able to infer copy number variants accurately. Application of the proposed method to a breast cancer dataset helps to identify genomic regions significantly associated with the disease.

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Genome-wide combination profiling of copy number and methylation offers an approach for deciphering misregulation and development in cancer cells

Cited by 8 publications

References 47 publications

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

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

Genetic and Epigenetic Somatic Alterations in Head and Neck Squamous Cell Carcinomas Are Globally Coordinated but Not Locally Targeted

A Single-Array-Based Method for Detecting Copy Number Variants Using Affymetrix High Density SNP Arrays and its Application to Breast Cancer

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