PHARMACOGENETICS AND BREAST PART 1
Pharmacogenomics is the study of genetic variations between
individuals to predict the risk of toxic side effects and the probability
that a patient will respond to single- or multidrug chemotherapy.
Breast cancer remains one of the most common cancers among
women worldwide and is second only to lung cancer in cancer-
related death. A better understanding of the mechanisms of
initiation and progression of breast cancer is needed for early
diagnosis and development of better therapeutic methodologies.
Differences in cancer patients' responses to chemotherapy have often
been attributed to pathogenesis and severity of the disease, drug
interactions, patient's age, gender, nutritional status, organ
functions and tumor biology. It is now well recognized that genetic
variations in drug target genes, disease pathway genes and drug
metabolizing enzymes can have greater influence on drug efficacy
and toxicity. In addition, germline variants can be used to study
breast cancer susceptibility, as well as the variable response to both
drug and radiation therapy used in the treatment of breast cancer.
This review discusses clinically relevant individual gene variations
that influence breast cancer susceptibility and cancer therapy, as
well as the microarray-based expression profiling studies that have
great potential in cancer pharmacogenomics in terms of tumor
classification, drug and biomarker discovery and drug efficacY
Pharmacogenomics and single nucleotide
Pharmacogenomics is the study of how genetic variations
influence responses to drugs. Genetic variations in drug-
metabolizing enzymes, transporters, receptors and other
drug targets have significant effects on the efficacy and
toxicity of many drugs. Pharmacogenomics combines
traditional pharmaceutical sciences such as biochemistry
with annotated knowledge of genes, proteins and single
nucleotide polymorphisms (SNPs). It is believed that drugs
might one day be tailor-made and adapted to each
individual's genetic makeup. Although factors such as
environment, diet, age, lifestyle and state of health can
influence an individual's response to medicines, their
genetic make-up is the key to creating personalized drugs
with greater efficacy and safety.
SNPs are the most frequently found DNA sequence
variations in the human genome, compared with infrequent
variants (mutations), the primary cause of genetic disorders.
It is believed that SNPs may contribute significantly to
genetic risk for common diseases [4••]. It is estimated that
the average nucleotide diversity is 1 difference/1200
basepairs. Approximately 1 million SNPs are likely to occur
in human genes, with approximately 500,000 being non-
coding SNPs, 200,000 being silent coding SNPs and 200,000
being replacement coding SNPs . SNPs found in the
coding and regulatory regions of genes are likely to be the
most relevant variants. Efforts to identify all SNPs and their
relevance to disease (cancer) susceptibility and treatment
outcome are continuous, and may take several more years.
However, the approach taken by many scientists at present
is the candidate gene approach in which one examines the
SNPs of the chosen gene that are likely to have an effect.
Single gene variations in pharmacogenomics
Single gene variation studies of both SNPs and mutations
are of use in predicting the risk of cancer development and
predicting drug efficacy and toxicity.
Predicting the risk of developing breast cancer
The lifetime risk of a woman developing breast cancer is
approximately 10% . Approximately, 5 to 10% of breast
cancers are of hereditary origin and two major genes
associated with hereditary breast and ovarian cancer, breast
cancer susceptibility gene 1 (BRCA1) and breast cancer
susceptibility gene 2 (BRCA2), have been identified [6••,7••].
Mutations in either of these genes confer a lifetime risk of
developing breast cancer of between 60 and 85% .
However, mutations in these genes account for
approximately 40% of hereditary breast cancer and only 2 to
3% of all breast cancer. Additional breast cancer
susceptibility genes with high-penetrance alleles are
believed to exist [9,10•]. Breast cancer also occurs in a
number of multicancer syndromes, such as Li-Fraumeni
syndrome, Li-Fraumeni-like syndrome, Cowdens syndrome,
Peutz-Jeghers syndrome and Muir-Torre syndrome, in
which affected individuals inherit mutations in p53, hCHK2,
PTEN, STK11/LKB1 and MSH2/MLH1, respectively [11-15].
Studies of BRCA1 and BRCA2 signaling pathways are
discovering newer genes that also appear to play important
roles in breast cancer susceptibility.