Genetic testing in the genomics era — the new frontier of personalised medicine

Published in Health News and Evidence

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The rapid pace of advancements in genome sciences is moving genetic testing into the medical mainstream. Once the domain of clinical geneticists or other specialists, as advances in personalised medicine revolutionise healthcare, genetic testing increasingly spans all areas of medicine, giving rise to a growing need for all health professionals to be informed. Direct-to-consumer marketing of tests further contributes to this need, as health professionals are more likely to be confronted with questions about these services or the results provided. GPs have a role in ensuring the community has access to accurate and appropriate information about the risks and benefits of genetic testing. As the genetic contribution of more diseases becomes known, genetic testing is destined for the medical mainstream. Are you ready?

Advances in genome sciences

Traditionally, medical genetic tests were ordered by clinical geneticists for rare genetic disorders, with interpretation of results and management of discussions with patients undertaken by specialised testing laboratories. The completion of the Human Genome Project introduced the era of genome sciences, delivering with it technological advancements that have been key enablers for the emergence of personalised medicine. While the healthcare of most individuals has not yet been affected, the promise of a revolution in healthcare is on the horizon.1

Increasingly, genetic testing spans multiple medical specialities as diagnostic tools for personalised medicine continue to evolve. Coupled with this has been an expansion of private companies offering direct-to-consumer (DTC) genetic tests that bypass the medical profession. Health professionals need to be equipped with reliable and accurate information about personalised medicine and DTC genetic tests so that patients can be informed about the risks and benefits associated with genetic tests.

The promise of personalised medicine

Personalised medicine refers to the tailoring of medical treatment to the specific characteristics of each patient. While delivering individualised care is a hallmark of modern medicine, personalised medicine takes this a step further by offering the possibility to predict predisposition to disease, influence decisions about lifestyle choices and tailor medical practice based on an individual’s genetic background.2

The approach is to stratify patients according to disease susceptibility or likely response to a particular treatment. In so doing the objective is to reduce the burden of disease by targeting preventive or therapeutic interventions more effectively, reducing unnecessary and costly treatments in those unlikely to respond and avoiding harmful side effects.3

A first step towards this goal is to understand all relevant forms of genetic variation in people and to interpret this information in a clinically meaningful way.4

Towards understanding genetic variation

Across the spectrum from rare disorders to common and complex disorders, the basis for the genetic contribution to disease arises from DNA sequence variation.5 At present, only a small fraction of the heritability of common diseases has been identified.1 Large-scale cataloguing of common and functional aspects of sequence variation is underway to characterise fully the genetic contribution to disease.6–8

Sequence variation arises as a result of mutations that occur at a low but constant rate in a DNA sequence. Most changes occur with no effect on gene function and are not associated with disease. Mutations that arise in germ-line tissues (cells that give rise to gametes) are inherited and increase genetic variation in populations. This may result in clinically significant loss of function or may be sufficient to cause disease.

Other mutations occur in somatic cells and accumulate spontaneously over time or through interaction with the environment. These cause relatively small changes in function and are not heritable but may contribute to disease in individuals. For example, some cancers are caused by the accumulation of somatic variants with age.

The cause of most common disease is multifactorial, with varying contribution from:

•    inherited and spontaneous mutations

•    complex interactions between mutations in one or more genes

•    effects of environment, lifestyle and chance.

Genome-wide association studies (GWAS) and deep sequencing studies have yielded an increasing number of disease-specific DNA markers that may prove clinically useful as biomarkers of disease, susceptibility to disease or variation in treatment response. As a diagnostic tool for personalised medicine, the biomarkers are based on identifying the mutations themselves, or their downstream expression products (mRNA) or end products (proteins or variant proteins). The presence of these biomarkers, or their activity, forms the basis for test outcome.

Molecular diagnostics

Molecular diagnostics may be predictive of the risk of developing a disease, or informative about its progression or severity. Others support treatment optimisation and are classified under the emerging field of pharmacogenomics, which seeks to identify genetic variants that underlie differential drug responses.

Pharmacogenomics offers great potential for personalised medicine but to date the translation of research findings into clinical practice has been incomplete. For example, although there is substantial evidence associating genetic variation with warfarin dose adjustment, there are few randomised trials showing better outcomes in clinical practice.9

Some examples of genetic tests that have been successfully adopted in clinical practice are summarised below. This is not an exhaustive list and is provided only to demonstrate the range of applications of genetic testing for personalised medicine. Although many of these tests involve conditions likely to be under the care of specialists, GPs may be involved in the ongoing care for patients with some of these conditions.

Genetic-based tests with clinical utility for personalised medicine

Disease/drug Genetic basis Rationale for testing Clinical utility
Predictive Inherited susceptibility to breast cancer and ovarian cancer BRCA1, BRCA2 Where a family-specific mutation has been identified, mutations in these genes increase the risk of developing cancer Carriers of the mutation can be screened by regular breast examination and annual mammography. Ovarian cancer screening is not recommended. Risk-reduction surgeries may be considered10
Lynch syndrome, or hereditary non-polyposis colon cancer MLH1, MSH2, MSH6 and PMS2 Where a family-specific mutation has been identified, mutations in these genes increase the risk of developing Lynch syndrome Carriers of the mutation can be screened by full colonoscopy every 1–2 years from age 25 or 5 years earlier than the age of diagnosis of the youngest affected family member11
Pharmaco-genomics Breast cancer susceptible to trastuzumab or lapatinib distosylate Over-expression of HER2 in tumour tissue Targeted therapy for HER2-positive breast cancer Trastuzumab is a costly drug and significant side effects outweigh the potential benefits in tumours that are not HER2-positive.12 Trastuzumab and HER2 testing are subsidised through the MBS
Metastatic colon cancer susceptible to cetuximab KRAS Targeted therapy for wild-type KRAS tumours that are likely to benefit from cetuximab Identifying patients unlikely to benefit from cetuximab before starting treatment.13 Cetuximab and KRAS testing are subsidised through the MBS
HIV treatment with abacavir HLA-B*5701 allele Patients with the HLA-B*5701 allele taking abacavir are at an increased risk of a potentially fatal hypersensitivity reaction (Stevens–Johnson syndrome) Although reactions occur rarely in the absence of HLA-B*5701, the presence of HLA-B*5701 is highly predictive of hypersensitivity. Genetic screening is routinely administered before starting abacavir.14 Abacavir and HLA-B*5701 testing are subsidised through the MBS
Metastatic melanoma susceptible to vemurafenib BRAF*V600E allele Targeted therapy for tumours expressing the BRAF*V600E allele, which responds to treatment with vemurafenib Identification of patients likely to benefit from vemurafenib before initiating treatment.15,16 MBS listing for vemurafenib and BRAF*V600E testing has been deferred

† A similar hypersensitivity reaction in response to allopurinol therapy has been reported to occur in some carriers of the HLA-B*5801  allele and is featured in this issue of NPS Direct17
MBS = Medicare Benefits Schedule

Direct-to-consumer tests

DTC tests offer information on ancestry and other applications unrelated to health, but advertising of health-related DTC tests is increasingly widespread. The clinical utility of DTC testing is unclear. A recent report found insufficient evidence to support the usefulness of genomic profiling for determining genetic risk for common diseases or for disease prevention.18 At present there are no evidence-based guidelines to support GPs confronted with questions relating to DTC tests, and little precedence for their medicolegal position in interpreting genetic tests obtained through DTC providers. Recently the National Health & Medical Research Council (NHMRC) sought feedback on a draft document providing advice to GPs about DTC tests.19

Both the Australian Medical Association (AMA) and the NHMRC recently released position statements advocating the involvement of medical practitioners, a robust evidence base and consumer information and support in relation to DTC genetic testing.20,21

In Australia, in vitro diagnostic devices for human genetic testing, including devices intended specifically for the collection of genetic samples, are classified by the Therapeutic Goods Administration (TGA) as having a high individual risk and are regulated accordingly.22 DTC genetic tests are increasingly available for purchase over the internet from overseas companies that are not subject to Australian quality standards or regulatory authority.

The authority of the TGA does not extend to regulating devices and their associated services outside of Australia. The NHMRC recommends that health-related genetic testing should be conducted in an accredited Australian laboratory with professional involvement and support.23

Limitations of genetic testing

There are a number of medical, psychological, social and ethical risks associated with genetic testing. This is in large part because genetic information is both personal and shared with family members and because the predictive value is uncertain. There are also different levels of risk depending on the purpose for which the genetic test is undertaken. Some tests, for example, predictive tests associated with the identification of a heritable mution in an apparently unaffected person, carry more risk due to interpretative, ethical or consent issues that require specialist involvement. Obtaining a detailed family history and discussing the medical and ethical significance of the result with patients is important when considering genetic tests.24

Practice points for GPs

  • Be aware of the ethical, legal and social issues resulting from genetic testing and consult with or refer to specialist services for clarification of genetic issues, risk assessment, counselling, diagnosis, testing and support.25
  • Inform the patient about the purpose, as well as personal and family implications of a genetic test before obtaining consent.25
  • Be aware that genetic counselling is not the same as providing information. In the case of predictive genetic tests, genetic counselling by a trained professional is required before and after the test, and after a positive genetic carrier test or in the case of an abnormal result.24
  • Genetic testing may benefit some patients and their families; it may also cause harm — the patient may require sensitive management and genetic counselling.19
  • Be aware of relevant support groups that may be useful regarding specific conditions; promote their service and encourage patients to make contact with them.25
  • Be aware that patients who have had a predictive or pre-symptomatic genetic test have a duty to inform life insurers of the test result when applying for a new, or altering an existing, policy.25
  • There is no legal duty to inform relatives of a patient about a positive genetic test result. Encourage and support the patient to share the information with their relatives.25
  • Have up-to-date information about genetic technologies ready to give to patients who raise concerns and refer patients to relevant and reliable sources for futher information.25
  • Consult accurate and detailed information about DTC tests taken by patients, including assessing the credibility of the company providing the tests. The NHMRC advocate that GPs cannot be expected to know about every DTC genetic test available but should investigate further when patients make enquiries.19

Further information

  1. Collins F. Has the revolution arrived? Nature 2010;464:674–5. [PubMed]
  2. National Health and Hospitals Reform Commission. A Healthier Future for all Australians - Final Report. 2009.$File/CHAPTER%201.pdf (accessed 19 November 2012).
  3. President's Council of Advisors on Science and Technology SoPM. Priorities for personalized medicine: Report of the President's Council of Advisors on Science and Technology. 2008. (accessed  19 November 2012).
  4. Lee C, Morton CC. Structural genomic variation and personalized medicine. N Engl J Med 2008;358:740–1. [PubMed]
  5. Burke W. Genomics as a probe for disease biology. N Engl J Med 2003;349:969–74. [PubMed]
  6. The International HapMap Project. Nature 2003;426:789–96.
  7. The 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 2012;491:56–65. [PubMed]
  8. The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012;489:57–74. [PubMed]
  9. Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011;90:625–9. [PubMed]
  10. National Breast and Ovarian Cancer Centre. Advice about familial aspects of breast cancer and epithelial ovarian cancer: a guide for health professionals. 2010. (accessed 22 November 2012.
  11. Australian Cancer Network Colorectal Cancer Guidelines Revision Committee. Guidelines for the Prevention, Early Detection and Management of Colorectal Cancer. Sydney: The Cancer Council Australia and Australian Cancer Network, 2005. (accessed  22 November 2012).
  12. Bilous M, Morey AL, Armes JE, et al. Assessing HER2 amplification in breast cancer: findings from the Australian In Situ Hybridization Program. Breast Cancer Res Treat 2012;134:617–24. [PubMed]
  13. Ibrahim EM, Zekri JM, Bin Sadiq BM. Cetuximab-based therapy for metastatic colorectal cancer: a meta-analysis of the effect of K-ras mutations. Int J Colorectal Dis 2010;25:713–21. [PubMed]
  14. Therapeutic Guidelines Limited. HIV antiretroviral drugs: dosing and adverse effects. 2012. (accessed 22 November 2012).
  15. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366:707–14. [PubMed]
  16. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16. [PubMed]
  17. Lee MH, Stocker SL, Anderson J, et al. Initiating allopurinol therapy: do we need to know the patient's human leucocyte antigen status? Intern Med J 2012;42:411–6. [PubMed]
  18. Janssens AC, Gwinn M, Bradley LA, et al. A critical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalize health interventions. Am J Hum Genet 2008;82:593–9. [PubMed]
  19. National Health and Medical Research Council. Assessing the direct-to-consumer genetic testing results of your patient – a quick guide for general practitioners. 2012. (accessed 22 November 2012).
  20. The Australian Medical Association Ltd. Position Statement on Genetic Testing. 2012. (accessed 23 November 2012).
  21. National Health and Medical Research Council. DNA genetic testing in the Australian context: A statement from the National Health and Medical Research Council. 2012. (accessed 22 November 2012).
  22. Therapeutic Goods Administration. Overview of the new regulatory framework for in-vitro diagnostic medical devices (IVDs). 2009. (accessed 23 November 2012).
  23. National Health and Medical Research Council. Direct-to-Consumer DNA Genetic Testing: An information resource for consumers. 2012. (accessed 22 November 2012).
  24. National Health and Medical Research Council. Medical genetic testing - Information for health professionals. 2010. (accessed 30 November 2012).
  25. Genetics education in Medicine Consortium. Genetics in Family Medicine: The Australian Handbook for General Practitioners. 2007. (accessed 23 November 2012).