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

Pharmacogenomics and Laboratory Medicine
99
TABLE 5.1
Types of Genetic Variations and Methods of Detection
Type Feature Method of Detection Example
Polymorphism
SNP Single nucleotide Sequencing, PCR
CNV
Repeats of a few DNA
base pairs
Sequencing, PCR
Mutations Single or a few base pairs Sequencing, PCR,
RFLP
Large deletions and
Array CGH, MLPA
duplications
VNTR in TPMT
CYP2D6
BCRA1 deletion
Gene amplification One or more copies of a gene FISH, RT-PCR Her2
Chromosomal level
rearrangements
Translocation
Chromosome study,
FISH
BCR–ABL in
CML
Inversion
Chromosome study,
FISH
ALK1
Note: CNV, copy-number variation.
copying one or more times. A frameshift mutation refers to the addition or loss of
DNA base pairs that alter the reading frame (a group of three bases) of a gene,
resulting in a nonfunctional protein or premature stop codon. Insertions, deletions,
and duplications may all cause frameshift mutations. Because frameshifts and premature
stop codons are typically deleterious in nature, these alterations are interpreted
as disease-causing mutations per ACMGG recommendations for Standards
for Interpretation and Reporting of Sequence Variations (Richards et al. 2008).
Polymorphisms are differences in individual DNA that are not mutations. Single
nucleotide polymorphisms (SNPs) are the most common form of polymorphisms,
defined as the occurrence at an allele frequency of at least 1/1000 bases in the general
population (Sachidanandam et al. 2001). There are an estimated 1.4 million SNPs
in the human genome, some of which contribute to the variability in drug response
and adverse effects, including pharmacokinetic and pharmacodynamic processes.
Mutations and SNPs can be detected by molecular biology methods, such as direct
sequencing or PCR, followed by restriction enzyme digestion (also known as restriction
fragment length polymorphism, or RFLP), and gel electrophoresis.
Genetic differences also occur in a manner of the small deletion or duplication,
large deletion or duplication, or rearrangement. Larger deletions and duplications
often include one or several genes. This type of genetic variation is also known as
copy-number changes at the chromosome level. Other genetic rearrangements at the
chromosomal level include translocation or inversion. A chromosome translocation
is caused by rearrangement of parts between nonhomologous chromosomes. A gene
fusion may be created when the translocation joins two otherwise-separated genes,
whose occurrence is common in cancer. The most famous example is the BCR-
ABL fusion gene that results from a translocation between chromosomes 9 and 22,