Epigenetics was introduced and defined by C.H. Waddington as ‘the causal interactions between genes and their products which bring about the phenotype into being’¹. An updated definition is, ‘heritable changes in gene expression that do not involve any alteration in DNA sequence’^3,4. The term ‘epigenomics’ is often used instead of ‘epigenetics’ to reflect the wider use of molecular methods. Epigenetic changes such as DNA methylation and histone deacetylation (epimutations) are important in the control of gene expression. Disruption of epigenetic control is now thought to underlie many human diseases, including cancer and some serious adverse drug effects ⁴. For example, silencing of the PTEN promoter, has recently been suggested as the cause of cancer in patients with the Cowden syndrome, a familial cancer syndrome ⁵. Such suppression of gene transcription by methylation or acetylation is referred to as epigenetic silencing.

References

1. Waddington CH. Preliminary Notes on the Development of the Wings in Normal and Mutant Strains of Drosophila. Proc Natl Acad Sci U S A 1939;25(7):299-307.
2. Holliday R. The inheritance of epigenetic defects. Science 1987;238(4824):163-70.
3. Holliday R. Epigenetics: a historical overview. Epigenetics 2006;1(2):76-80.
4. Esteller M. Epigenetics in cancer. N Engl J Med 2008;358(11):1148-59.
5. Bennett KL, Mester J, Eng C. Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. Jama 2010;304(24):2724-31.

Genomics is the use of modern molecular methods to interrogate the genome, the complete genetic make-up of a cell, individual, or population. The results of such research is increasingly used to inform the practice of medicine; hence the term Genomic Medicine. Applications include investigations of the aetiology, classification, prediction and management of disease on the basis of the genome-wide data.

References

1. Science and Technology Committee. Genomic Medicine. London: House of Lords; 2009.

The germline of an adult is the line of germ cells that have genetic material, which can be passed on to a child. The sperm and the ovum form part of the germline as are all the precursors which lead to them, including the gametocytes and the zygote. Non-germline cells are called somatic cells. Germline gene mutations are those that are heritable. This term is widely used in the cancer literature to identify mutations that are passed on to a child by its parents ¹. Examples are the BRCA1 and BRCA2 gene mutations, which increase the risk of breast cancer. Many other such germline mutations have now been identified for a range of other familial cancers (hereditary and seen frequently in close family members)¹. Most cancers are sporadic (arising spontaneously) and thought to be due to exposure to environmental insults (e.g. melanoma from excessive sun exposure, lung cancer due to cigarette smoke, and colonic cancer due to dietary toxins) but the importance of genetic predisposition, through germline gene mutations, is increasingly being recognised. It may well be that most cancers have a familial influence. Retinoblastoma is a cancer well-recognised for presenting both in familial and sporadic forms. What may be confusing is that in the cancer literature, the presence of germline mutations is usually assessed using DNA from somatic cells of healthy tissues. Their germline origin is inferred from follow-up studies of familial associations.In contrast to germ-line mutations, somatic gene mutations involve mutations of genes in cells other than those of the germline. Early work, which showed that malignant activation of a K-ras oncogene, occurred in lung carcinoma but not in normal tissue of the same individual established the importance of somatic mutations driving growth of cancer cells ².

References

1. Grann VR, Jacobson JS. Population screening for cancer-related germline gene mutations. Lancet Oncol 2002;3(6):341-8.
   2. Santos E, Martin-Zanca D, Reddy EP, Pierotti MA, Della Porta G, Barbacid M. Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science 1984;223(4637):661-4.

Personalized medicine is choosing treatment or disease prevention strategy, specifically for the individual patient. Over recent years, the term has evolved to mean the use of molecular genetic information to tailor such therapy. This includes the identification of molecular features of host, parasite or cancer cell, which help to predict the patient’s risk-category and likely response to therapy, either beneficially or adversely.The US Genomics and Personalized Medicine Act of 2007 defines personalised medicine as ‘The application of genomic and molecular data to better target the delivery of healthcare, facilitate the discovery and clinical testing of new products, and help determine a person’s predisposition to a particular disease or condition’.Stratified medicine is the use the patient-specific genomic information, with other patient-specific factors such as age and menopausal status, to stratify people into discrete groups with a view to optimising prevention or treatment of disease. This forms the basis for defining inclusion criteria for formal evaluation of treatments in randomised controlled trials. Trusheim who coined the term, defined it as the use of one or more clinical biomarkers (surrogate outcome measures for the clinical outcome of interest) to identity therapies more suited for specific populations of patients. For example, lung cancer patients with mutation in the EGFR gene (the biomarker) in the tumour cell are more likely to respond to the drug gefitinib.

 References:

1. Genomics and Personalized Medicines Act. In: S976. 110th Congress 1st session; 2007.
2. Trusheim MR, Berndt ER, Douglas FL. Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nat Rev Drug Discov 2007;6(4):287-93.

Pharmacogenetics is the study of the influence of heredity on drug response - that is, how genetic differences between individuals may cause them to respond differently, both beneficially and adversely, to a particular drug. The more recently coined term ‘Pharmacogenomics’ is used interchangeably but some commentators suggest that the latter more appropriately reflects recent emphasis on molecular methods and the simultaneous study of the influence of multiple genes on drug response. The Science and Technology Committee of the House of Lords defined ‘Pharmacogenetics’ as ‘the study of the way in which a particular gene or small number of genes affects drug metabolism or responsiveness’ and Pharmacogenomics’ as the study of the way in which genetic variation across the genome affects drug metabolism and responsiveness’.

Reference:

Science and Technology Committee. Genomic Medicine. London: House of Lords; 2009.