Genome-wide association studies of cancer

Abstract

Knowledge of the inherited risk for cancer is an important component of preventive oncology. In addition to well-established syndromes of cancer predisposition, much remains to be discovered about the genetic variation underlying susceptibility to common malignancies. Increased knowledge about the human genome and advances in genotyping technology have made possible genome-wide association studies (GWAS) of human diseases. These studies have identified many important regions of genetic variation associated with an increased risk for human traits and diseases including cancer. Understanding the principles, major findings, and limitations of GWAS is becoming increasingly important for oncologists as dissemination of genomic risk tests directly to consumers is already occurring through commercial companies. GWAS have contributed to our understanding of the genetic basis of cancer and will shed light on biologic pathways and possible new strategies for targeted prevention. To date, however, the clinical utility of GWAS-derived risk markers remains limited.

Fig 1.

Phenotypic effect size and frequency of occurrence. (*) Named genes only reflect the most likely candidate genes to be implicated by the marker single nucleotide polymorphisms (SNPs) identified from the genome-wide association studies. (†) The marker SNPs mapping to JAK2 in myeloproliferative neoplasms and KITLG in testicular germ cell tumors have odds ratios of approximately 3.0, with allele frequencies ranging from 20% to 40%.

Fig 2.

Familial risk of common cancers. Most common cancers, including breast, colorectal, and prostate cancer, exhibit familial aggregation, with the disease being more common in family members than in the general population. While familial aggregation may be secondary to genetic or environmental factors, evidence from monozygotic twins of patients suggests that genetic factors are mainly responsible.^, As demonstrated in this figure, known high-penetrance cancer predisposition syndromes explain only a fraction of the familial risk of cancer.^– While genome-wide association studies have identified numerous low-penetrance loci for each of these three common cancers, their contribution to the familial risk of cancer remains limited and a large portion of the familial risk of these cancers remains unexplained. GWAS, genome-wide association study; SNP, single nucleotide polymorphisms.

Fig 3.

Genome-wide association study (GWAS) design. A typical cancer GWAS starts with the selection of a large number of individuals affected with a specific type of cancer and a suitable comparison group without cancer. DNA is isolated from each individual and genotyped using commercially available genome platforms (ie, chips) that assess for common genetic variations in the form of single nucleotide polymorphisms (SNPs) across the entire human genome. Data are reviewed to ensure appropriate genotyping quality. In phase I, stringent statistical methods are used to assess for associations between SNPs passing quality thresholds and cancer risk. In phase II, SNPs found to be significantly associated with cancer risk (approximately 5% to 10% of all SNPs) are tested in a larger set of independent patients and controls using arrays containing the putative SNPs of interest. Some studies proceed to further evaluation of putative SNPs in a third phase using larger and more heterogeneous populations to confirm the genotype associations.