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

130 Applying Pharmacogenomics in Therapeutics
all 14 genes. Specific-site analysis is available for individual gene mutations known
to be in the family.
Currently, multiplex genetic testing is offered by Ambry Genetics and other commercial
or academic laboratories for inherited cancer susceptibility for several types
of cancers, including breast, colorectal, ovarian, pancreatic, and more. Multiplex
genetic testing for inherited cancer susceptibility is particularly useful when there
is significant genetic heterogeneity or there are difficulties to predict which gene
may be mutated based on personal phenotype or family history. In some instances,
NGS on the whole exome may also reveal mutations in genes that increase the risk
of developing cancer. However, multiplex testing or even Sanger sequencing for a
single gene or a few genes will also detect variants with limited supporting evidence
or conflicting evidence to classify as mutation or benign variants. These variants
are usually classified as variant with unknown significance (VUS). It is important
for clinicians and patients to understand the significance of findings of mutations
(including mutations and variants like pathogenic), VUS, and benign or negative.
Pretest and posttest genetic counseling is recommended for all patients who undergo
genetic testing.
SUMMARY
The first clinical observations of genetic variations in drug response were documented
in the 1950s, involving the tuberculosis drug isoniazid that is metabolized
by NAT2. These early studies gave rise to the field of pharmacogenetics and later
pharmacogenomics. Pharmacogenomics is now a branch of pharmacology to study
genetic variants affecting drug metabolism, transport, molecular targets/pathways,
and genetic susceptibility to the diseases. Advances in genetic study and testing,
particularly advances in DNA sequencing technologies, greatly increase the pace of
pharmacogenomic study and application in clinical settings. The accomplishment
of the whole human genome sequencing in 2003 provided the complete mapping
and better understanding of all human genes and drove the development of DNA
sequencing technologies. The cost to sequence the whole genome has dropped significantly
due to the development and application of “next-generation” and “thirdgeneration”
sequencing technologies. Although the cost has stayed flat for the past
couple of years, it is believed that sequencing cost per genome will drop below $1000
per genome in the near future. High throughput and lower cost in NGS technologies
have profound influence on the realization of pharmacogenomics into the realm of
clinical practice. Obviously, there are a dramatic number of challenges on interpreting
and translating the genetic testing results into clinical practice. Regulations and
guidelines are needed to implement pharmacogenomics into patient care. For example,
a combined effort from the American Society of Clinical Pathology, College of
American Pathologists (CAP), Association for Molecular Pathology, and American
College of Medical Genetics and Genomics is currently working on guidelines
for molecular testing for selection of CRC patients for targeted and conventional
therapy. CAP and the American Society of Hematology published guidelines for
molecular testing of acute leukemia. Whole exome sequencing is currently being
performed in clinical genetic testing practice. The next step in pharmacogenomics