What are the opportunities for personalised medicine in rare disease and cancer?

Personalised medicine is the practice of tailoring diagnostics and therapeutics to the individual. The DNA sequence within each cell is the genome.

Despite any two people sharing over 99% of this DNA sequence, it is the unique DNA sequences within this genome that enable individualised care. These alterations in the DNA sequence are called mutations.

The field of genomics aims to identify and capitalise on these mutations with notable successes in diagnosing and managing rare diseases and cancer.

The field of genomics is rapidly coming to prominence. In 2016, the Chief Medical Officer for England, Dame Sally Davies, declared this to be 'Generation Genome'¹ and the NHS has been moving towards integrating genomics into everyday healthcare.

Ambitious projects such as The 100,000 Genomes Project are bringing discussions about genomics to the clinic, and many clinicians are finding themselves fielding challenging questions about this rapidly moving technology.

Research remains integral to clinical practice and, as such, new diagnostic tests can emerge with novel targets being identified for cutting-edge therapies.

Inherited genetic syndromes are caused by alterations to the DNA called mutations. The mutations can be inherited (germline mutations) or they can occur spontaneously as new 'de novo' mutations. While all cells carry the mutation, the effect is most pronounced in tissues that rely on the correct functioning of these mutated genes.

Cancer is rarely caused by inherited genetic changes. Most cancers are caused by mutations that are acquired throughout life in mature cells. These are called somatic mutations and occur naturally as a consequence of damage to DNA. These mutations cannot be inherited or passed on.

While the DNA of each cell is prone to damage that can result in somatic mutations, the DNA has safety mechanisms to repair the damage. However, if the damage is too great or the safety mechanisms are impaired, somatic mutations that lead to cancer can persist.

Most cancers are caused by mutations that are acquired throughout life in mature cells.

Tobacco carcinogens act to induce higher mutation rates in lung tissue². The vast majority of these somatic mutations make no real impact on the way cells work. Often these are repaired and if not, they simply persist in the genome throughout the cellular generations, akin to a genetic scar.

Occasionally, one of these mutations may be so detrimental to the cellular function that the cell fails to survive. Even less frequently, the impact of the mutation gives the cell additional functions to better survive and replicate.

When an advantageous mutation is acquired, it can grow and replicate, which leads to similar mutations. The cumulative gain of these somatic mutations results in a population of cells that outgrow and outcompete the rest of the population. This malignant growth manifests as a tumour.

Identifying mutations can be achieved through DNA sequencing³. If a mutation is thought to be within a specific set of genes, sequencing of these regions alone can be performed.

When no obvious genes are causing the clinical features identified, a broader approach can be taken by sequencing each of the protein-coding genes in the human genome. This provides an insight into 2% of the human genome and is called whole exome sequencing.

For a more comprehensive approach, the genes and the DNA sequences around them can be investigated through whole genome sequencing. While whole exome and whole genome sequencing are becoming commonplace, these approaches generate large amounts of data and require expert analysis.

Identifying mutations could provide a long-awaited diagnosis for a rare syndrome or highlight a potential therapeutic target in a cancer.

Buried within this data may lie pathogenic mutations. To identify these novel targets in rare diseases, the patient’s sequenced DNA can be compared to their parents’ DNA. By removing the shared regions of DNA, only the de novo mutations remain.

De novo mutations are often the cause of rare developmental disorders. For cancer, the same process can be performed by comparing the tumour genome (DNA extracted from the cancer cells) with the patient’s genome (often DNA from blood cells).

The impact of these mutations in the tissues of interest can then be modelled through computational simulations (in-silico analysis) and functional studies (in zebrafish for example), as well as by comparing with reports in other rare disease families or patients.

Together, the multi-disciplinary team of clinicians and scientists can consider all of the evidence and produce a joint opinion as to whether the mutations identified can explain the clinical syndrome. This result could provide a long-awaited diagnosis for a rare syndrome or highlight a potential therapeutic target in a cancer.

Genomic diagnoses can shape precision management of rare diseases. One example is Neonatal Diabetes Mellitus (NDM).

This genetic syndrome is caused by severe β-cell dysfunction in the pancreas and presents often before patients are 6 months old⁴. Currently, there are causative variants identified in 25 known genes. New genomic sequencing technology has revealed 5 distinct genetic subtypes of NDM (Table 1) and empowered clinicians to provide a single genetic test that gives a diagnosis for ~80% of patients⁴.

The importance of these genetic subtypes stretches beyond just diagnosis. Due to the unique pathogenesis associated with each subtype, the management of each condition varies from simple oral therapies to organ transplants. Therefore, the most appropriate care can be delivered to the patient purely based on a single mutation in a single causative gene (Table 1).

Table 1 – The five genetic subtypes of neonatal diabetes mellitus with illustrative causal genes and their respective optimal therapies⁴.

A mainstay of the workup of non-small cell lung cancer is the identification of potential genetic targets.

In adenocarcinomas, the overexpression of EGFR (epidermal growth factor receptor) promotes cellular growth and drives cancer progression. This is driven by mutations or duplications in the EGFR gene⁵.

Sequencing the DNA from a tumour can highlight aberrations in the genetic code and reveal the tumour to be susceptible to treatment with EGFR-inhibitors such as erlotinib and gefitinib.

There is support available in the community for genomics education. GatewayC is a free cancer education initiative designed for primary care professionals. Further genomics e-learning resources are available for NHS clinicians through the Royal College of General Practitioners (RCGP) and the e-LFH Hub (Genomics Education Programme). FutureLearn also offers a free online course for genomic scenarios in primary care.

Additionally, genetic medicine departments have a valuable and diverse multi-disciplinary team including clinical geneticists, genetic counsellors and clinical scientists. Consultations typically cover concerns about personal or family experience of genetic conditions, their inheritance and optimal clinical care and we would encourage GPs to consider referrals to use this national clinical service.

Being aware of the rapid progress in genomic medicine and the core principles can empower you to support patients.

GPs are uniquely placed at the heart of patient care – particularly for those rare disease patients and their families on long diagnostic odysseys. Keeping up with this advancement is challenging, but being aware of the rapid progress in this field and the core principles can empower you to support patients through this journey while anticipating any questions and problems they may have. These may be focused around the concepts of genetics, the principles of testing or providing overviews of therapies available.

We encourage those in primary care to enquire and research into this burgeoning field of genomics whilst also utilising the expert and approachable multi-disciplinary team within genetic medicine and oncology.

Personalised medicine is demonstrating notable success in the diagnosis and management of rare diseases and cancer. We've summarised everything you need to know below.

1. Genetic tests can end the diagnostic odyssey for rare genetic diseases.
2. DNA sequencing can highlight mutations in the cancer genome that may be of diagnostic and therapeutic potential.
3. Genomics moves quickly, but a sound grasp of core principles empowers the GP to provide a holistic and personalised approach to care.
4. Referrals to the Genetic Medicine Service are welcome and a large number of services are available.
5. The multi-disciplinary team within oncology can provide support and insight for those in primary care.

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