UHO Pharmacogenetics & Stratified Medicine Glossary

Glossary of Medical & Genetic Terminology Used in the Module

Abacavir Drug used for the treatment of HIV infection in combination with other antiretroviral drugs. Class of Drug: Reverse Transcriptase Inhibitor. Adenocarcinoma A malignant tumour derived from glandular structures in epithelial tissue & cells. Amplification A cancer genetic term; a genetic alteration/mutation that results in many copies of a small (< than a few megabases) DNA segment of the genome. Apoptosis Programmed cell death; in response to a stimulus, a pathway is triggered that leads to the destruction of the cell by a characteristic set of reactions. Carcinoma A malignant tumour derived from epithelial tissue & cells. Codeine/Codeine Phosphate A pro-drug used in the management of mild to moderate pain. It is metabolized to morphine (the active metabolite). The rate of metabolism from pro-drug to active metabolite varies between individuals. Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia is an inherited condition present from birth (congenital). The adrenal gland is larger than usual (hyperplasia). It is described as an inborn error of metabolism because the body is missing a normal copy of an enzyme that stimulates the adrenal glands to release the cortisol hormone. Cystic Fibrosis & CFTR Cystic fibrosis (CF) is an inherited disease which mainly affects the lungs and digestive system. These organs are impaired with thick, sticky mucus which can lead to symptoms like a cough, chest infections and difficulty absorbing and digesting fat in food; it is a multi-system disorder that results in a general failure to thrive. It is described as an inborn error of metabolism because the body is missing a normal copy of a protein encoded by the CFTR gene which lies on chromosome 7. The encoded protein, the cystic fibrosis transmembrane conductance regulator (CFTR) is responsible for regulation of sodium, chloride and bicarbonate transport in many tissues of the body.

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UHO Pharmacogenetics & Stratified Medicine Glossary

Cytochrome P450 (CYP) Family A highly polymorphic family of phase I enzymes (important for the liver metabolism of prescribed drugs and other compounds). One protein encoded by the gene CYP2D6 metabolises ~ 25 % of all prescribed drugs and about 70 different genetic variants (alleles) have been described. There is inter-ethnic variation in the allele frequencies and while some alleles are associated with poor or no enzyme activity, others result in very high rates of drug metabolism and so low plasma concentration of prescribed drugs. Carbamazepine A medication that is mainly used for the treatment of epilepsy and neuropathic pain. It is also used for some psychiatric disorders. It works as an anti-convulsant by blocking some nerve responses in the brain. Dexamethasone A medication used to treat many disorders including inflammatory & allergic conditions; congenital adrenal hyperplasia; and the nausea and vomiting associated with chemotherapy treatment. It is a long-acting corticosteroid that reduces the formation, release, and activity of chemical mediators of inflammation. Diploid Genome The human genome is a set of human genetic information that is stored as DNA sequences. The diploid genome comprises 46 human chromosomes; a paired set of 23 chromosomes inherited from each parent. The diploid genome is found in the somatic cells (body cells as opposed to the germ cells) and has twice the DNA content as the haploid human genome. Driver mutation A cancer genetic term; a mutation that directly or indirectly confers a selective growth advantage to the cell in which it occurs. Epigenetic change Variations in gene expression that are not caused by changes in the DNA sequence but do include chemical modifications to chromatin and DNA, such as methylation. DNA molecules are methylated by the addition of a methyl group to carbon position 5 on cytosine bases that are positioned adjacent to a guanine base (CpG sites). Transcription, the conversion of DNA to messenger RNA (mRNA), is usually repressed by DNA methylation and histone de-acetylation. Epigenetic modifications during

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UHO Pharmacogenetics & Stratified Medicine Glossary tumorigenesis can lead to the wrong gene being switched on or off, for the given physiological circumstances or for the given tissue type. Founder effects Founder members of particular new populations may be carriers of mutant alleles for some traits (recessive or late-onset dominant) and so within that population these alleles are at a higher frequency than in the wider population. Genome Wide Association Study (GWAS) A study design that involves the analysis of thousands or millions of polymorphic markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease. Typically, the genetic results from research participants with a defined disease are compared with the genetic results from a matched control cohort. Once new genetic associations are identified, researchers can use the information to develop better strategies to detect, treat and prevent the disease. Such studies are particularly useful in finding genetic variations that contribute to common, complex diseases, such as heart disease and mental illnesses. Haploid Genome The human genome is a set of human genetic information that is stored as DNA sequences. The haploid human genome can be found in the egg and sperm cells and comprises 23 human chromosomes. The haploid genome has about three billion DNA base pairs. Oncogene A cancer gene. Genes usually become oncogenes by a mutation that gives them a new or increased function, e.g. ABL gene, ERBB2 gene, RAS genes, MYC genes. Penetrance The chance that a genotype yields the expected phenotype (non-penetrance: a clinically normal individual carries the mutant genotype). Pharmacogenetics Describes how genetic factors can affect the action of drugs; both their clinical benefit and adverse effects. Pharmacogenomics is defined similarly but generally refers to how DNA based technologies can be used to predict response; leading to personalized or individually stratified protocols for the use of medicine. Polygenic inheritance

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UHO Pharmacogenetics & Stratified Medicine Glossary

The inheritance and expression of a phenotype being determined by many genes at different loci; each allele exerting a small additive effect. Traits that show a continuous distribution, such as blood pressure and height, are often determined by the interplay of many alleles at different loci. Multifactorial Disorders Require the interaction of environmental and additive genetic factors to become manifest. Single Gene (or Monogenic) Disorders Caused by defects in one particular gene, and often have simple and predictable (Mendelian) inheritance patterns. Single nucleotide polymorphism or SNP A site in the genome where the DNA sequences of many individuals vary by a single base. Somatic In the body, as opposed to germline. Most of the mutations that are involved in the development and progression of cancer occur in somatic cells; i.e. they are acquired throughout life rather than as inherited mutations. Splicing A genetic term describing the production of (diverse) messenger RNA molecules by the differential cutting and joining of molecules from a single precursor RNA. Statins A commonly prescribed medication used to treat raised cholesterol and to reduce the risk of cardiovascular disease. These are lipid-lowering drugs that inhibit the enzyme HMG- CoA reductase. This enzyme plays a central role in the production of cholesterol. Transcription The production of messenger RNA (mRNA) from a DNA template. Translation The synthesis of a protein sequence from a messenger RNA (mRNA) sequence. Trastuzumab A breast cancer treatment that interferes with a receptor protein (HER-2) over expressed because of an oncogene (ERBB2) mutation. Trastuzumab is a monoclonal antibody treatment used for patients with tumours that express high levels of HER-2 because of the underlying “driver” oncogene mutation. Translocation

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UHO Pharmacogenetics & Stratified Medicine Glossary

A genetic term for a specific mutation/rearrangement where regions from two non- homologous chromosomes are joined. Tumour suppressor gene (TSG) Often genes that normally prevent or put checks on cell division (control the cell cycle) or genes involved in apoptosis; TSGs are lost or inactivated in cancers. Examples include P53 & RB1. Warfarin Warfarin is an oral anticoagulant (a drug taken by mouth that stops blood from clotting). It is used to reduce the risk of blood clots; heart attacks; and strokes. Warfarin inhibits the vitamin-K dependent synthesis of blood clotting factors.

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