Genomic and epigenomic profiling in cancer
Authors: Hiroyuki Aburatani
Journal: Clinical Cancer Research (2007)

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

CN06-04 

Any individual cancer is not identical. Recent advances in genomic and epigenomic analysis are leading to a molecularly based reclassification of cancer, and hopefully will create many opportunities for improved cancer treatment, including accelerating development of novel therapeutics.      Information on genome, epigenome, proteome and gene networks (cistrome) must be integrated to elucidate the mechanism of cancer. In genomic analysis, we need to characterize genetic changes in tumor cells, as well as genetic variation. Human genome has more genetic variation than previously expected, including SNPs as well as non-SNP DNA variation, like copy number variation (CNV) (Redon, 2006). Meanwhile, DNA methylation is an epigenetic mark crucial in regulation of gene expression and lineage commitment. Epigenetics can explain reversible heritable changes in gene function that occur without a change in the DNA sequence, and must be involved in cancer. Recent progress in epigenetic analysis will be presented.    Epigenomic profiling     Most of previous studies on DNA methylation detection were not comprehensive, because only limited genomic regions, such as selected genes or promoter CpG islands, were analyzed, mostly with the use of methylation-sensitive restriction enzymes. Recently we have established a method for detection of DNA methylation using oligonucleotide tiling arrays, which, coupled with methylated DNA immunoprecipitation (MeDIP-chip), has enabled us to analyze comprehensive methylation profiles (Hayashi 2006).      Genomic landscape of DNA methylation and histone modification DNA methylation patterns in the HOXA gene cluster region were integrated with histone H3 and H4 acetylation patterns in HCT116 colon cancer cell line. Little histone acetylation was observed in the hypermethylated regions, demonstrating a reciprocal relationship between DNA methylation and histone H3 and H4 acetylation, i.e. active chromatin structure.    de novo DNA methylation in ES cell differentiation: To detect de novo DNA methylation in the establishment of chromatin structure during development, we measured the global methylation patterns during ES-cell differentiation to three different lineages, ecto-, meso- and endoderm. Methylation patterns were distinct among different lineages and will change dynamically during early embryogenesis.    Methylation marker: Using a tiling array covering 25,500 human promoter regions, MeDIP-chip analysis showed that methylation was not restricted in CpG islands, implicating the importance of unbiased analysis, and that its patterns were distinct among various tissues and between cancer versus normal tissues. It will be applied to efficiently search for epigenomic biomarkers for early cancer detection or cancer risk assessment, such as methylation in the promoter regions of SFRP genes in colon cancer.    Gene silencing: As an integrated approach to better elucidate a molecular basis of cancer, we have combined genomic and epigenomic profiles. Genotyping arrays were used to detect chromosomal aberrations in an allelic manner using Genome Imbalance Map algorithm (Ishikawa 2005) or GEMCA (Komura, 2006). We observed that uniparental disomy (UPD) is not a rare event and gives rise to loss of heterozygosity (LOH) in various cancers, which cannot be identified by the conventional array CGH analysis because UPD regions do not show any total copy number changes. While homozygous deletions detected within LOH regions in several tumors will be relevant in tumor progression, we also examined epigenetic silencing as described above. Currently, genome-wide screening in gastroenterological cancers for aberrant methylation in the LOH regions is under way to identify novel candidates for tumor suppressors.    References:    1) Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, Gonzalez JR, Gratacos M, Huang J, Kalaitzopoulos D, Komura D, Macdonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME. Global variation in copy number in the human genome. Nature . 444(7118):444-454. 2006    2) Komura D, Shen F, Ishikawa S, Fitch KR, Chen W, Zhang J, Liu G, Ihara S, Nakamura H, Hurles ME, Lee C, Scherer SW, Jones KW, Shapero MH, Huang J, Aburatani H. 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