DNA and disease

Learn about how variations in DNA can increase the risk of developing certain diseases, like cancer and heart conditions

Your genome ­– your body’s complete set of genetic material – is made up of more than six billion units (nucleotides) of DNA divided across 46 chromosomes.

The sequence of these units is important. Your body uses sections of DNA (genes) to make proteins and other molecules that it needs to function. Each set of three nucleotides in a gene corresponds to a particular amino acid – when your body reads the sequence of a gene, the corresponding amino acids are assembled into a chain to make a protein.

Differences in your DNA sequence contribute to your individuality, and also affect the way your body functions. These differences are known as variants.

Variants in genes can change the product that is made – they might cause the gene to produce a non-functioning protein, or sometimes no protein at all.

Variants can be inherited from your parents, or arise when DNA is copied as your cells divide. Most are harmless, but some can cause or increase your risk of diseases. 


Genetics of cancer

What does it mean to say that cancer runs in someone’s family?

Everyone has an individual risk of cancer that is influenced by an interaction of several factors – including their age, lifestyle and genes. Sometimes, similar patterns of exposure to things like cigarette smoke or UV radiation can cause similar types of cancer to be present among family members.

But around 5-10% of the time, clustering of cancer in a family is due to inherited genetic causes.

Somatic and germline variants

Cancer is caused by variants in a person’s DNA that affect how cells function, especially how they grow and divide. Sometimes, cancer is caused by only one variant with a large effect on cells, but most of the time it is caused by a build-up of multiple variants with small effects. This is one of the reasons why a person’s cancer risk increases with age.

The majority of cancer-causing variants are somatic – they occur at some point after a person is born, and affect cells in the body other than sperm or egg cells. Somatic variants are not heritable and cannot be passed on through families. They can be caused by environmental factors, ­like radiation and cigarette smoke, or sometimes occur randomly as a cell divides.

A small proportion of the time, cancer develops due to inherited – or germline – variants. These variants are present in sperm or egg cells, and are passed on through families. Germline variants tend to have large effects on cells, and usually cause people to be at a much higher risk of developing specific types of cancer than the general population. Germline variants often cause a cancer syndrome, meaning that they increase risk of more than one type of cancer, and sometimes non-cancerous conditions as well.

Variants that increase cancer risk are found in two main types of gene – proto-oncogenes and tumour suppressor genes.


The usual function of proto-oncogenes is to make proteins that help cells grow and divide. Like all genes, proto-oncogenes can be switched on or off depending on how much of their particular product is required by the cell. Genetic variants can sometimes cause proto-oncogenes to be activated when they are not supposed to be, or even permanently switched on. When this occurs, the proto-oncogene becomes an oncogene and can cause cancer.

For example, the RET gene produces a signalling protein that is essential for the normal development of certain types of cells. Growth factors – molecules that stimulate cell growth – bind to this signalling protein and trigger the cell to make certain changes, such as dividing or taking on a specific function (differentiating). Variants in the RET gene can cause it to be overactive and express protein constantly, even when the cell might not need it. This can trigger cells to grow and divide in an uncontrolled way, leading to cancer.

Tumour suppressor genes

The role of tumour suppressor genes is to control critical processes in the cell, like repair of damaged DNA, or regulation of when a cell should divide. In this way, tumour suppressor genes prevent normal cells from becoming cancer cells.

Many of the most widely studied cancer genes are tumour suppressors with involved in DNA repair – including TP53BRCA1 and BRCA2.

The p53 protein binds to DNA to guide
how a cell responds to damage (top).
Genetic variants can alter the structure
of p53, meaning it is no longer able to
bind to DNA (bottom).This can cause
mistakes in DNA to build up over 
time, leading to cancer.  

TP53 produces a protein, p53, that repairs damage to DNA throughout the body. DNA can be damaged in multiple ways – mistakes can be made when the DNA sequence is copied during replication, or exposure to UV radiation or carcinogenic chemicals can cause the DNA strands to physically break.

When DNA is damaged, such as by exposure to UV radiation or carcinogenic chemicals, p53 is activated. The p53 protein binds directly to DNA and helps guide how the cell responds to the damage. If the damage can be repaired, p53 recruits repair proteins that can fix it. If repair is not possible, p53 triggers the destruction of the cell (apoptosis).

Variants in the TP53 gene are found in more than half of human cancers. can cause p53 to not function properly. Without this crucial protein, cells with damaged DNA may continue to grow and divide as normal, rather than being destroyed. As these cells accumulate more and more damage over time, they become more susceptible to changing into cancer cells.

BRCA1 and BRCA2 also have crucial roles in repairing DNA, particularly the repair of double-stranded breaks. Hundreds of variants have been identified that disrupt the activity of BRCA1 or BRCA2 , which means that mistakes in DNA are left to build up over time. This greatly increases a person’s risk of cancer, particularly breast and ovarian cancer.

People with a strong family history of cancer can have genetic testing to look for variants in high-risk genes, such as BRCA1 and BRCA2, or even across the whole genome. Knowing the specific gene that is affected is important – this knowledge can be used to estimate a person’s risk of developing cancer in their lifetime, which in turn can help guide the management of their health.

For more information on the genetics of cancer visit yourgenome.org


Genetics of heart conditions

Your genes control every aspect of the cardiovascular system, including the muscle contractions needed for your heart to beat, the strength of your blood vessels, and the structure of the chambers of your heart. 

If a gene involved in the cardiovascular system contains a variant, this can interfere with its normal activity and cause symptoms – a heart condition. Heart conditions that are passed on through genes are known as inherited heart conditions. While common diseases like coronary artery disease can have a genetic component, this is usually in the form of multiple genetic variants each conferring a small increased risk. Inherited heart conditions are caused by one or a few variants that have big effects on health, and these conditions are much more rare.

Inherited heart conditions can be broadly grouped based on the area of the heart they affect. The role of the affected gene in the body determines the type of heart condition a person develops. 

Ion channel proteins control
the beating of the heart by
transporting charged ions in
and out of the cell. 
In long QT syndrome (yellow),
genetic variants cause a
shortened amino acid chain
that produces an ion channel 
protein that cannot transport
ions effectively. This can lead
to an irregular heartbeat.

Structural heart conditions

These are problems with the structures that make up the heart – its muscles, vessels and valves. For example, cardiomyopathies are diseases of the heart muscle. The most common form, hypertrophic cardiomyopathy, affects up to 1 in 200 people.

Hypertrophic cardiomyopathy causes a thickening of the heart muscle and subsequent narrowing of the chambers of the heart, which can make it harder for the heart to pump blood. The condition has variable penetrance, meaning that some people with hypertrophic cardiomyopathy will have no symptoms, while others will develop serious complications like heart failure or sudden death.

Variants in more than 13 genes have been linked with hypertrophic cardiomyopathy. The most commonly involved genes – MYH7, MYBPC3, TNNT2 and TNNI3 – encode proteins that form sarcomeres, the basic structural units that make up muscle tissue. Sarcomeres give structure to heart muscle, and regulate contractions. A variant in one of these genes may alter the structure of or reduce the amount of sarcomere proteins in the cell. However, it is not yet clear exactly how these changes to the sarcomere cause the symptoms of hypertrophic cardiomyopathy, or why some people are less affected than others.  

Electrical heart conditions

Electrical heart conditions cause problems with the way the heart beats – known as arrhythmias – and are most often caused by changes in the structure or function of ion channels. These are proteins located in the cell membrane that control the transport of charged ions into and out of the cell. This movement of ions controls the beating of the heart – positive sodium ions enter the cell and create a depolarisation (a change in the overall charge of the cell) that causes the heart muscle to contract. Then, potassium channels open, positive ions move back out of the cell, and the cell begins to repolarise as it returns to its negatively charged resting state. This process repeats every time the heart beats.

Long QT syndrome is a condition that affects how long the repolarisation phase lasts – how long the heart takes to recharge after each heartbeat. It can be caused by variants in a number of genes, including KCNQ1, which encodes a potassium ion channel protein. More than 600 variants in KCNQ1 have been linked with long QT syndrome, and the functional effect of many of these is not known. Some variants alter the structure of the channel, while others produce a functioning channel that is degraded before it reaches the cell membrane. The result is a cell that is less effective at transporting potassium ions, which can increase the length of time that heart cells take to repolarise. In some cases, this can lead to ventricular fibrillation, a serious arrhythmia characterised by fast, chaotic heartbeats.


For more information and support for families affected by inherited heart conditions, visit the Australian Genetic Heart Disease Registry.