Single nucleotide polymorphisms, usually referred to as SNPs, are small genetic changes, single base nucleotides in DNA (individual As, Ts, Gs, or Cs), that vary among individuals. Human populations are estimated to be 99 percent identical at the level of genetic sequence. Diversity arises from the remaining 1 percent variation, most of which are accounted for by SNPs.
There are approximately 10 million SNPs in the human genome. They are found, on average, every 100 to 300 base pairs in the 3-billion-base pair genome, although their density varies between regions. SNPs are found in both coding and non-coding regions and the majority of them - two out of every three - are substitutions of thymine (T) for cytosine (C).
SNPs are relatively stable evolutionarily, and are, therefore, useful in population studies. Also, because SNPs are distributed more or less evenly throughout the human genome, they can serve as helpful landmarks in the construction of genetic maps.
SNPs in Cancer
Although the majority of SNPs are silent, they can have important consequences for individual susceptibility to disease and reactions to medical treatment.
In cancer, SNPs in the genes BRCA1 and BRCA2 that inactivate these tumor suppressors occur in 5 percent of all breast cancer cases and also put carriers at risk for developing ovarian cancer.
SNPs in the tumor suppressor p53 can result in Li-Fraumeni syndrome and the LF-like syndrome, rare heritable conditions that predispose to the development of malignancies including osteosarcoma, liposarcoma, leukemia and meningioma.
Evidence also indicates that SNPs in several other genes, including MPO and NAT1 and NAT2, predispose a patient toward lung cancer, bladder cancer and colon cancer.
Scientists are also trying to determine how the presence or absence of SNPs affects response to drug treatments in a research subfield called pharmacogenomics.
In 2008, researchers published data that found patients with breast cancer who were treated with letrozole had much better outcomes if they had the SNP rs4646. Specifically, the time to progression among the patients with this SNP was 17.2 months compared with 6.4 months in the patients without the SNP.
A similar study published in 2007 found no relationship between the presence of SNPs and the effect of docetaxel in prostate cancer.
Research Cooperation
Efforts to develop SNP maps, catalogs of SNPs and their genomic locations, have been initiated by the U.S. Human Genome Project and the SNP Consortium, a large group of pharmaceutical companies partnering with the U.K. philanthropy, the Wellcome Trust.
In 1998, as completion of the Human Genome Project was in sight, the Department of Energy and the National Institutes of Health Human Genome Program drew up plans to develop SNP maps as the next step in delineating a functional understanding of the genome. Their goals were defined as: develop technologies for rapid, large scale scoring of SNPs; identify common variants in the coding regions of most known genes; create SNP map of 100,000 markers; develop intellectual foundations for sequence variation studies; and create public resources for DNA samples and cell lines.
The SNP consortium was established in 1999, with the Wellcome Trust partnering with ten international pharmaceutical companies, including AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Novartis and Pfizer. The project's initial goal was to generate a list of 300,000 markers, but it has uncovered 1.5 million markers to date.
Recently, the U.S. Food and Drug Administration encouraged pharmaceutical companies to track and publish SNP data for patients enrolled in clinical trials. The hope is that drugs that are only effective on a small subset of study populations - those individuals carrying a particular SNP - might be brought to light, whereas if SNP data are not collected, those drugs would appear to be unsuccessful.
The Cancer Genome Anatomy Project (cpag.nci.nih.gov) is an effort promoted by the National Cancer Institute and the National Genome Research Institute designed to collect comprehensive data regarding the mutations found in human cancers and to make this information available in a public database. It includes in the SNP500Cancer project, which aims to examine 102 reference samples to locate SNPs of immediate importance to molecular epidemiology studies in cancer.
A related project, the International HapMap Project, aims to develop a haplotype map of the human genome, the HapMap, which will describe the common patterns of SNPs seen in human DNA populations. The HapMap, which will be made publicly available www.hapmap.org, is a collaboration among scientists in Japan, the U.K., Canada, China, Nigeria and the United States.