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.

Proto-oncogenes

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 TP53, BRCA1 and BRCA2.

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