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Single nucleotide polymorphisms, or SNPs, are single base pair variations in our DNA that can have profound impacts on our health and susceptibility to various diseases, including cancer.
These tiny genetic differences, which occur at specific locations within our genome, can alter the function or expression of genes involved in critical cellular processes such as DNA repair, cell cycle regulation, and metabolism. As our understanding of the complex relationship between SNPs and cancer risk continues to grow, so too does the potential for personalized risk assessment and targeted prevention strategies.
One of the most well-studied examples of a cancer-associated SNP is the BRCA1 and BRCA2 mutations. These SNPs, which are inherited in an autosomal dominant fashion, confer a significantly increased risk of breast and ovarian cancer. Women who carry a BRCA1 mutation have a 72% lifetime risk of developing breast cancer and a 44% risk of ovarian cancer, while those with a BRCA2 mutation have a 69% and 17% risk, respectively (Kuchenbaecker et al., 2017). These SNPs disrupt the normal function of the BRCA proteins, which play a crucial role in repairing double-stranded DNA breaks and maintaining genomic stability.
Another important example of a cancer-associated SNP is the rs6983267 variant in the 8q24 region of the genome. This SNP has been consistently associated with an increased risk of colorectal cancer, with individuals carrying two copies of the risk allele having a 1.5-fold higher risk compared to those with no risk alleles (Haiman et al., 2007). The 8q24 region is a gene desert, meaning it does not contain any known protein-coding genes. However, this region is thought to contain regulatory elements that influence the expression of nearby genes, such as the MYC oncogene, which is frequently overexpressed in colorectal and other cancers.
SNPs can also influence cancer risk by altering the metabolism and detoxification of carcinogens. For example, the GSTM1 and GSTT1 genes encode enzymes that help eliminate harmful substances from the body, such as polycyclic aromatic hydrocarbons found in tobacco smoke. SNPs that result in null alleles of these genes, meaning they produce no functional enzyme, have been associated with an increased risk of lung, bladder, and head and neck cancers, particularly among smokers (Karageorgi et al., 2011). These findings underscore the complex interplay between genetic susceptibility and environmental exposures in shaping cancer risk.
In addition to these well-established examples, numerous other SNPs have been implicated in cancer risk through genome-wide association studies (GWAS). These studies scan the entire genome for SNPs that are more common in individuals with a particular cancer compared to healthy controls. For example, a GWAS of prostate cancer identified over 100 SNPs associated with increased risk, many of which are located near genes involved in androgen signaling, cell cycle regulation, and DNA repair (Schumacher et al., 2018). While the individual effect sizes of these SNPs are often small, they can add up to significantly influence an individual's overall risk.
As our knowledge of cancer-associated SNPs continues to expand, so too does the potential for personalized risk assessment and targeted prevention strategies. By genotyping individuals for a panel of known risk SNPs, it may be possible to identify those at highest risk and offer them enhanced screening, chemoprevention, or lifestyle interventions. However, it is important to recognize that SNPs are just one piece of the complex puzzle of cancer risk, which is influenced by a multitude of genetic, environmental, and lifestyle factors.
Moreover, the clinical utility of SNP-based risk assessment remains to be fully established, and there are important ethical and psychosocial considerations to be addressed. Individuals found to carry high-risk SNPs may experience increased anxiety, depression, or discrimination, and there may be disparities in access to genetic testing and preventive care. As such, the integration of SNP-based risk assessment into clinical practice will require a thoughtful and multidisciplinary approach that prioritizes patient autonomy, informed decision-making, and equitable access to care.
In conclusion, SNPs play a crucial role in shaping an individual's risk of developing various types of cancer. By understanding the complex interplay between these genetic variations and other risk factors, we may be able to develop more personalized and effective strategies for cancer prevention and early detection. However, the clinical application of SNP-based risk assessment is still in its early stages, and much work remains to be done to ensure its ethical and equitable implementation. As the field of cancer genetics continues to evolve, it will be important to balance the promise of precision medicine with the need for patient-centered care and social justice.
References:
Haiman, C. A., Le Marchand, L., Yamamato, J., Stram, D. O., Sheng, X., Kolonel, L. N., Wu, A. H., Reich, D., & Henderson, B. E. (2007). A common genetic risk factor for colorectal and prostate cancer. Nature Genetics, 39(8), 954-956. https://doi.org/10.1038/ng2098
Karageorgi, S., Prescott, J., Wong, J. Y. Y., De Vivo, I., & Kraft, P. (2011). GSTM1 and GSTT1 copy number variation in population-based studies of endometrial cancer risk. Cancer Epidemiology, Biomarkers & Prevention, 20(7), 1447-1452. https://doi.org/10.1158/1055-9965.EPI-11-0190
Kuchenbaecker, K. B., Hopper, J. L., Barnes, D. R., Phillips, K.-A., Mooij, T. M., Roos-Blom, M.-J., Jervis, S., van Leeuwen, F. E., Milne, R. L., Andrieu, N., Goldgar, D. E., Terry, M. B.,
Rookus, M. A., Easton, D. F., & Antoniou, A. C. (2017). Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA, 317(23), 2402-2416. https://doi.org/10.1001/jama.2017.7112
Schumacher, F. R., Al Olama, A. A., Berndt, S. I., Benlloch, S., Ahmed, M., Saunders, E. J., Dadaev, T., Leongamornlert, D., Anokian, E., Cieza-Borrella, C., Goh, C., Brook, M. N., Sheng, X., Fachal, L., Dennis, J., Tyrer, J., Muir, K., Lophatananon, A., Stevens, V. L., ... Haiman, C. A. (2018). Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nature Genetics, 50(7), 928-936. https://doi.org/10.1038/s41588-018-0142-8