The Human Genome Project identified the sequence of the human genome and is the foundation of our understanding of how DNA instructions lead to a functioning human. Continued genomic research has sought to build on this foundation, evaluating questions surrounding:
- the function of genes and the elements that regulate them;
- variations in DNA sequences among individuals and their significance;
- protein structures and functions; and
- DNA/protein interactions with each other and the environment
Specifically, several international initiatives have been undertaken to evaluate the genetic profile of patient populations and identify patterns associated with disease risk and therapeutic response. Further research efforts are underway to develop new strategies to use these genomic differences for disease detection and monitoring.
Edward S. Kim MD, shares his thoughts on the potential impact that the "Moonshot Initiative" may have on genomic and bio-marker development.
The Cancer Genome Atlas
The Cancer Genome Atlas is a project initiated by the NIH and the National Human Genome Research Institute to sequence specimens from multiple disease sites and learn more about the genomic alterations associated with cancer. This program is coming to a close after analyzing more than 30 types of cancer and specimens from more than 100,000 patients, and creating a database and multidimensional maps for researchers worldwide. More than 1,000 studies and publications from this program have helped to form everyone’s understanding of cancer.
Edward S. Kim MD, discusses how the Cancer Genome Atlas' research efforts have affected our understanding of genes regarding cancer treatment.
Genome-wide association studies
A genome-wide association study (GWAS) is an approach to compare the genomes of people with or without a disease and identify genetic variations called single-nucleotide polymorphisms, or SNPs (pronounced “snips”), which are associated with the disease. A SNP is a nucleotide variation at a single position in the genome within a population typically found at more than 1%. While most SNPs are a normal DNA variation having no negative health effects, some SNPs may influence health factors such as disease risk or drug response. SNPs are distinguished from a mutation in which a disease-causing mutation occurs in less than 1% of the population, typically in the coding or regulatory region of a gene affecting the function of the resulting protein.
GWAS use technologies to evaluate hundreds to millions of SNPs at the same time. As new SNPs or combinations of SNPs are linked with a disease, researchers use these data to identify the genes associated with the disease. These data can also be leveraged to identify markers of disease risk and develop new strategies to detect, monitor or treat the disease.
Examples of these studies include:
Large-scale genotyping identifies 41 new loci associated with breast cancer risk
Michailidou K, et al. Nat Genetics. 2013;doi:10.1038/ng.2563.
Analysis of a patient population from 9 GWAS including 10,052 breast cancer cases and 12,575 controls of European ancestry was performed. A total of 29,807 SNPs were genotyped with data analysis identifying SNPs at 41 loci, a specific location of a gene, DNA sequence or chromosome that were associated with susceptibility to breast cancer. This study represents one of the largest cancer GWAS and substantially increases the number of identified breast cancer susceptive loci.
Large-scale association analysis in Asians identifies new susceptibility loci for prostate cancer
Wang M, et al. Nat Commun. 2015;doi:10.1038/ncomms9469
A large-scale meta-analysis of two GWAS was performed with a Japanese population consisting of 1,583 prostate cancer cases and 3,386 controls and a Chinese population consisting of 1,417 prostate cancer cases and 1,008 controls. Replication in three independent sample sets was also performed to verify the results. Two loci were identified that indicated susceptibility for prostate cancer, with the loci corresponding to two genes, PPFIBP2 and ESR2. Additional experiments assessed the mRNA levels of these corresponding genes, and confirmed differential expression in prostate tumors compared with paired normal tissues for PPFIBP2 and ESR2.
Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil of FOLFOX administration
Fernandez-Rozadilla C, et al. Pharmacogenomics J. 2013;doi: 10.1038/tpj.2012.2.
A large-scale meta-analysis of two GWAS was performed with a Japanese population consisting of 1,583 p
A GWAS was performed on 221 patients with colorectal cancer treated with 5-fluorouracil (5-FU) either alone or in combination with oxaliplatin (FOLFOX) followed by validation in 791 additional patients. Seven SNPs were identified that were associated with adverse drug reactions.
International HapMap Project
The International HapMap Project is an international scientific effort to identify patterns of human genome variation and determine those that impact health and disease as well as response to drugs or environmental factors. SNPs clustered together on a chromosome are inherited from a single parent as a block, with the pattern of SNPs on a block known as a haplotype. The term haplotype is a combination of the words haploid, or cells with a single set of chromosomes, and genotype, or the genetic composition of an organism. HapMap is a map of these haplotype blocks across broad genomic regions, and presents information on their locations in the genome and their frequency in different populations across the world. HapMap reduces the data complexity by consolidating the SNPs shared within a haplotype allowing genetic variations to be searched indirectly by using a small set of variants that distinguish a haplotype to assess variations in genes, chromosome regions or broader DNA regions. Genomic studies using this data are potentially more efficient for identifying regions of detectable disease-associated markers.
Encyclopedia of DNA Elements Project
Launched by the National Human Genome Research Institute in 2003, the Encyclopedia of DNA Elements (ENCODE) project was designed to expand the information from the Human Genome Project. Whereas the Human Genome Project sequenced the DNA that makes up the human genome, the goal of ENCODE is to identify the functional and regulatory elements in the human genome sequence including proteins and noncoding RNA molecules.
By mapping regions of transcription, transcription factor association, histone modification and chromatin structure, researchers have been able to associate a biological function to approximately 80% of the human genome. These efforts include not only previously characterized protein coding regions but also regions external to protein coding areas considered to be candidate regulatory elements such as noncoding RNAs, alternative splice transcripts and regulatory sequences. The regulatory regions determine if a gene is expressed, activating or repressing cellular signals. Several of these noncoding functional elements have been correlated with disease-associated SNPs, highlighting the strength of these approaches to identify new biological factors associated with disease.
Additional genomics research efforts
In addition to genomic DNA regions, there is substantial evidence that RNA including messenger RNA and noncoding RNA, such as microRNA (miRNA), may also serve as an effective disease diagnostic. Studies have identified changes in RNA expression associated with malignancy and tumor progression, or drug response. Efforts are also underway to develop drugs that target miRNAs and selectively block their activity.
With ongoing technological and bioinformatics improvements, significant advances have been made in the area of disease diagnosis and monitoring in circulating body fluids such as blood, plasma/serum, urine and cerebral spinal fluid. Research efforts highlight the potential to diagnose disease, or monitor for indicators of drug response or disease progression based on the DNA signatures in circulating tumor cells, circulating tumor DNA (or cell-free DNA) or extracellular RNA.
Further clinical efforts have also focused on a variety of variables such as pharmacogenomics studies to match the right drug and therapeutic dose to a patient based on his or her molecular markers. Patient financial burden is also a critical area of interest with efforts focused on how to implement precision medicine in a cost effective strategy.
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