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Chapter 8 Pharmacogenomics and Hematologic Diseases 81

this has helped to identify so-called tagging (tag) SNPs. Such tagging SNP catalogues have been used in GWASs to pinpoint genes
SNPs can be used to predict with high probability the alleles at other important to diseases and drug responses, and in the past few years
co-segregating “tagged” SNPs, and the number of identified tag SNPs more than 2000 robust associations with more than 300 complex
varies considerably among populations of different ancestry. Of note, diseases and traits have been identified. 9
common SNPs are also in LD with other common variants in the
human genome (e.g., structural variants [SVs]).
Variation in the Human Epigenome
STRUCTURAL GENOMIC VARIANTS Epigenetics encompasses inherited and acquired changes in gene
function that cannot be explained by alterations in sequence of
SVs are balanced or unbalanced changes in DNA content, and nucleic acids. The epigenome is a complex layer of regulatory
encompass alterations ranging from submicroscopic sequence vari- information that is superimposed on the genome (epigenetics literally
ants greater than 50 bp to larger, sometimes cytogenetically visible, means “above genetics”), with major mechanisms that contribute to
variants. Unbalanced DNA alterations that change the number of epigenetic variation including DNA methylation, DNA hydroxy-
base pairs in comparison with a reference genome are as frequent as methylation, and various histone modifications such as histone
or even more common than SNPs, and include copy number variants acetylation and methylation. As in medical genetics, many seminal
(CNVs) or smaller insertions/deletions (indels). Balanced variations discoveries in medical epigenetics were made during investigations of
such as inversions and translocations are less common. Many efforts hematologic diseases, and the myelodysplastic syndrome is considered
focus on the identification, validation, and mapping of these vari- a prototypical example of an epigenetic disease. In contrast to stable
ants, and the major catalogs are the Database of Genomic Variants sequence variants, the epigenetic cellular state is principally mal-
(DGV) and the Database of Genomic Structural Variation (dbVAR; leable and can be influenced by environmental factors such as diet
see Table 8.1). CNVs are found in a wide spectrum of genomic and toxin exposure. Of note, the expression of genes that encode
regions; therefore, many pharmacologically relevant genes can be important drug-metabolizing enzymes (e.g., cytochrome P450) and
affected by these variants. Indeed, CNVs have been described to drug transporters (e.g., solute carrier family) have been shown to be
influence activity of some of the most important drug-metabolizing altered via intrinsic and extrinsic factors that modify the epigenetic
3
enzymes, such as cytochrome P450 enzymes and glutathione signature, thereby influencing the disposition and effects of drugs.
S-transferases. 7 Moreover, the dynamic nature of epigenetics provides a mechanism
to modulate the expression of genes that influence drug sensitivity,
and so-called “epidrugs” (i.e., drugs that influence gene expression via
SOMATIC GENOMIC VARIANTS epigenetic mechanisms) have already been successfully incorporated
into the treatment of hematologic diseases (e.g., hypomethylating
Genomic instability is a hallmark of cancer cells. Nonrandom genetic agents such as decitabine and vidaza for myelodysplastic syndrome,
abnormalities, including aneuploidy (gains and losses of whole and histone deacetylase inhibitors such as vorinostat and romidepsin
chromosomes) and structural rearrangements that often result in the for cutaneous T-cell lymphomas). 3
expression of chimeric fusion genes (e.g., BCR–ABL1), can be found Major efforts are ongoing to generate detailed epigenenomic
in the majority of hematologic malignancies. These acquired (somatic) maps to provide a basis for understanding cellular processes, the
genomic variations can differ significantly from inherited (germline) pathogenesis of diseases, and alterations in drug responses, such as the
genomic variations and can, for example, create allele-specific copy Encyclopedia of DNA Elements (ENCODE) and the Epigenomics
number differences between normal host cells and cancer cells. Roadmap (see Table 8.1).
Such differences can have pharmacologically relevant consequences.
Indeed, it was shown that the cellular acquisition of additional GENETIC VARIATIONS INFLUENCING DRUG RESPONSE:
chromosomes in leukemia cells—for example, the gain of additional
chromosomes 21 in hyperdiploid ALL (>50 chromosomes)—can PHARMACOGENETICS–PHARMACOGENOMICS–
cause discordance between germline genotypes and leukemia cell PHARMACOEPIGENOMICS
phenotypes, which are important when these discordant genotypes/
phenotypes influence the disposition of antileukemic agents. More- Pharmacogenomics is a major element of the recently announced U.S.
over, somatic deletions of genes encoding proteins that regulate the President’s Precision Medicine initiative. Mostly empiric approaches
stability of the DNA mismatch repair enzyme mutS Homolog 2 are used to select drug therapy for most patients and most diseases,
(MSH2) have been identified in approximately 11% of children with despite the fact that there is great heterogeneity in the way people
newly diagnosed ALL. These deletions in ALL cells have been shown respond to medications, in terms of both host toxicity and treatment
to cause DNA mismatch repair deficiency and increased resistance to efficacy. Unfortunately, for almost all medications, interindividual
thiopurines, representing another genomic mechanism by which leu- differences are the rule, not the exception, and these differences result
kemia cells can acquire MSH2 deficiency and mercaptopurine (MP) from the interplay of many variables, including genetics and environ-
resistance. 8 ment. Variables influencing drug response include pathogenesis and
severity of the underlying disease being treated; drug interactions;
CATALOGUES OF GENOMIC VARIANTS, the patient’s age, sex, nutritional status, and renal and liver func-
GENOTYPING PLATFORMS, AND tion; the presence of concomitant illnesses; and other components
of treatment. In addition to these clinical variables, both inherited
GENOME-WIDE ASSOCIATION STUDIES and acquired (e.g., somatic mutations in cancers) genome variation
can influence the disposition and effects of medications, including
Cataloguing the pattern of genome variation in diverse populations many used to treat hematologic diseases. Clinical observations of
is fundamental in understanding areas of human phenotypic diversity inherited differences in drug effects (based on family studies and
such as interindividual and interethnic differences in drug responses; twin studies) were first documented in the 1950s, and the concept of
increasingly detailed maps of human genomic variation are provided pharmacogenetics was defined initially in 1959 by Friedrich Vogel as
in public databases (see Table 8.1). Information from these maps has “the study of the role of genetics in drug response.” The number of
been used to design high-throughput genotyping platforms (e.g., recognized clinically important pharmacogenetic traits grew steadily
SNP chips), thereby providing tools to interrogate the relationship in the 1970s; the elucidation of the molecular genetics underlying
between genetic variation across the human genome and important these traits began in the late 1980s and 1990s, with their translation
phenotypes such as disease or response to medications in a relatively to molecular diagnostics to guide drug therapy being well under-
unbiased (agnostic) fashion. 2 way in the 2000s. The study of pharmacogenetics began with the