Sunday, 8 September 2013

Cancer Genetics

Cancer genetics is a rapidly evolving field, which has revolutionized the practice of medicine in the past decade. Genetic testing for several high-penetrance tumor susceptibility genes such as BRCA1, BRCA2, and APC have allowed the identification of individuals at high risk for breast and colon cancers that can be effectively prevented with early screening. Somatically acquired genetic changes such as overexpression of the ERBB2 gene in breast cancer and mutations of the KRAS or BRAF genes in colorectal cancer are observed in a significant fraction of patients. These genetic alterations can be effectively targeted with antibodies such as trastuzumab and cetuximab. Treatment with these genetically targeted agents increases patient survival. Because genetic information allows for the exact identification of individuals, the widespread expansion of genetic testing is potentially fraught with ethical and legal issues.

Systematic studies of common genetic variants are facilitated by the fact that individuals who carry a particular SNP allele at one site often predictably carry specific alleles at other nearby sites. This correlation is known as linkage disequilibrium (LD); a particular combination of alleles along a chromosome is termed a haplotype. The correlations between causal mutations and the haplotypes on which they arose have long served as a tool for human genetic research: first finding an association to a haplotype and then subsequently identifying the causal mutation(s) that it carries. With the sequencing of the human genome and development of high-throughput genomic methods, it has become clear that the human genome generally displays more LD than under simple population genetic models, and that LD is more varied across regions, and more segmentally structured, than had previously been supposed. These observations indicated that LD-based methods would generally have a great value (because nearby SNPs were typically correlated with many of the neighbors), and also that LD relationships would need to be empirically determined across the genome by studying polymorphisms at high density in population samples. This has provided the rationale for the development of the International HapMap project (www.hapmap.org). Novel genotyping technologies combined with the knowledge generated by the HapMap project have provided the necessary tools to interrogate the association of genetic variants from the entire genome with risk for various diseases.



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