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.
0 comments:
Post a Comment