Genome-wide association studies in cancer--current and future directions

Abstract

Genome-wide association studies (GWAS) have emerged as an important tool for discovering regions of the genome that harbor genetic variants that confer risk for different types of cancers. The success of GWAS in the last 3 years is due to the convergence of new technologies that can genotype hundreds of thousands of single-nucleotide polymorphism markers together with comprehensive annotation of genetic variation. This approach has provided the opportunity to scan across the genome in a sufficiently large set of cases and controls without a set of prior hypotheses in search of susceptibility alleles with low effect sizes. Generally, the susceptibility alleles discovered thus far are common, namely, with a frequency in one or more population of >10% and each allele confers a small contribution to the overall risk for the disease. For nearly all regions conclusively identified by GWAS, the per allele effect sizes estimated are <1.3. Consequently, the findings of GWAS underscore the complex nature of cancer and have focused attention on a subset of the genetic variants that comprise the genomic architecture of each type of cancer, which already can differ substantially by the number of regions associated with specific types of cancer. For instance, in prostate cancer, there could be >30 distinct regions harboring common susceptibility alleles identified by GWAS, whereas in lung cancer, a disease strongly driven by exposure to tobacco products, so far, only three regions have been conclusively established. To date, >85 regions have been conclusively associated in over a dozen different cancers, yet no more than five regions have been associated with more than one distinct cancer type. GWAS are an important discovery tool that require extensive follow-up to map each region, investigate the biological mechanism underpinning the association and eventually test the optimal markers for assessing risk for a disease or its outcome, such as in pharmacogenomics, the study of the effect of genetic variation on pharmacological interventions. The success of GWAS has opened new horizons for exploration and highlighted the complex genomic architecture of disease susceptibility.

Synergistic Effects of Low-Risk Variant Alleles in Cancer Predisposition

“…These results suggests that studies with large sample sizes (5000 and higher) targeting SNPs will be a better strategy to identify causal disease SNPs [10]. Instead, genome wide association studies (GWAS) have emerged as an important tool for discovering regions of the genome that harbor uncommon genetic variants that confer risk for complex tumors, whose nature is probably polygenic [11]. These variants include single nucleotide variants (SNVs) or single nucleotide polymorphisms (SNPs), small insertions and deletions and structural genomic variants.…”

“…Second, the high bar of genome wide significance protects against the probability of a false-positive finding. The latter is critical because GWAS are discovery tools that point investigators toward long arduous follow-up studies for unraveling the underlying biology and the pursuit of markers for risk assessment [11,13]. However, the common cancer alleles detected by GWAS account for only 10% of the familial relative risk of disease.…”

“…Since each region confers a small contribution to the cancer risk, it is daunting to consider any single nucleotide polymorphism as a clinical test, rather one should think about the synergistic action of different SNP as well as the environmental factor [11,27]. These studies allowed researchers to identify large susceptibility chromosomal regions for many unrelated cancers.…”

“…These studies allowed researchers to identify large susceptibility chromosomal regions for many unrelated cancers. For example, the 8q24 region harbor multiple cancer susceptibility SNP loci associated with prostate cancer, colorectal cancer and precancerous colorectal adenomas, and bladder cancer risk; these loci affect genes such as MYC oncogene and the prostate stem cell antigen gene (PSCA) [11,28].…”

Development of two multiplex mini-sequencing panels of ancestry informative SNPs for studies in Latin Americans: an application to populations of the State of Minas Gerais (Brazil)

“…Currently, Affymetrix and Illumina commercial arrays allow to genotype up to ~10 6 markers scattered in the human genome, at a cost of few hundreds of US dollars per individual (Chung et al, 2010). Even if most of these single-nucleotide polymorphisms (SNPs) are not AIMs, with this resolution it is possible to estimate individual and chromosomal region ancestries with high accuracy.…”