Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

36 Applying Pharmacogenomics in Therapeutics
membrane–bound small GTPase signaling pathway, is the target for the drug
Vectibix ® or Erbitux ® in patients with metastatic colorectal cancer. However, these
drugs become ineffective if the KRAS gene contains point mutations at several positions
in certain colorectal tumor tissues (Stintzing 2014).
CNV is another form of genomic variation that involves relatively large genome
regions being deleted or duplicated on certain chromosome(s) (Iafrate et al. 2004;
Sebat et al. 2004). CNVs usually alter the copy numbers of multiple genes and
therefore might cause more severe consequences on gene expression, regulation,
and function than SNPs. An individual usually carries 4 million bases of CNVs
(1 in every 800 bp) (Kidd et al. 2008). Besides stable and heritable CNVs, de novo
CNVs are also present, which are confirmed by studies of identical twins. De novo
CNVs may arise through diverse mechanisms at various stages of development.
Like SNPs, some CNVs have been associated with disease susceptibility or drug
efficacy. For example, excessive expression or extra copies of the HER2 gene could
lead to a very aggressive breast cancer in patients. A monoclonal antibody drug,
Herceptin ® (trastuzumab), could effectively treat these cancer patients with HER2
overexpression. To date, many companion diagnostic tests have been approved by
the US FDA for various cancer treatments (http://www.fda.gov/). These tests reveal
specific genomic mutations in cancer patients and can greatly increase the success
rate of drug treatments by identifying and matching a patient’s genotype with the
target(s) of a given cancer drug.
Epigenetics is the study of biological changes that are not caused by changes in
DNA sequences. DNA methylation and histone modification are two major epigenetic
events and can control the on- and off-switch of gene expression. The pattern
of DNA methylation changes in development, aging, and certain diseases (Jones
and Baylin 2002; Singal and Ginder 1999). Like gene mutations or deletions, DNA
methylation frequently silences gene expression and could lead to aberrant function
of normal tumor suppressor(s). A better understanding of epigenetic mechanisms
underlying diseases has allowed therapeutic applications of DNA methylation
inhibitors, such as azacitidine (5-azacytidine; Vidaza ® , Pharmion Corp., Boulder,
Colorado) and decitabine (Dacogen, SuperGen, Inc., Dublin, California, and
MGI Pharma, Inc., Minneapolis, Minnesota). These drugs provide new and effective
options for patients.
Hence, a pharmacogenetic understanding of genomic variations (e.g., point mutations
and CNVs) and epigenetic changes in a patient will play an important role in
the age of personalized medicine.
MAJOR BIOTECHNOLOGIES IN PHARMACOGENETICS
Numerous biomedical technologies have advanced our knowledge of pharmacogenetics,
among which DNA sequencing and analysis methods are the major
driving forces. The chain-termination method (Sanger sequencing) (Sanger et al.
1977) and the less frequently used chemical sequencing method (Maxam–Gilbert
sequencing) (Maxam and Gilbert 1977) are first-generation DNA sequencing
technologies. The principle of Sanger sequencing is that DNA polymerase selectively
incorporates chain-terminating dideoxynucleotides during in vitro DNA