What are somatic mutations?

Researchers in the Somatic Genomics programme at the Wellcome Sanger Institute have spent over a decade uncovering what somatic mutations are, how they arise and how they influence health and disease. Their work is transforming our understanding of cancer, ageing and even how our tissues protect themselves from damage.

Every human starts life as a single fertilised egg containing two copies of the human genome, one from each parent. As that cell divides to form the 37.2 trillion cells that make up the body, its DNA is copied again and again. Each time, small errors can be introduced.

These DNA changes that occur after fertilisation are called somatic mutations. They differ from germline mutations, which are DNA changes you inherit from your parents – these are present in sperm or egg cells and can be passed on to your children.

Unlike inherited germline mutations, somatic mutations:

• Cannot be passed on to children.
• Accumulate throughout life, so not all cells in your body are genetically identical.
• Occur in every tissue, from skin to liver to brain.

There are many kinds of somatic mutations. Some are single letter changes in DNA; others are insertions, deletions or larger structural rearrangements of genetic code. There are also epigenetic changes – chemical tags such as DNA methylation – that alter gene activity without changing the sequence itself.

There are two main sources of somatic mutations – endogenous (internal) and exogenous (external) exposures.

Endogenous exposures

Cells naturally produce mutations during DNA replication or through normal metabolic activity. These endogenous processes run constantly and generate most of the mutations in our bodies. As we go through life, we are all subject to these processes, some of which are well understood, while the mechanisms underlying others remain unclear. Somatic mutations to some extent are present just because we are alive, so even if we were to avoid all exogenous exposures, a basic level of cancer would likely still exist in society just through endogenous mutational processes alone.

Exogenous exposures

Environmental factors can damage DNA and increase mutation rates. Two well-known examples are:

• Ultraviolet (UV) light hits the skin and causes DNA damage that is converted into somatic mutations. The mutation rate and burden in the skin is much higher than in most other cell types of the body because of the relentless exposure to DNA-damaging UV. This results in an increased risk of skin cancers.
• Tobacco smoke contains at least 60 different chemicals that can cause mutations. These chemicals result in an elevated mutation rate and burden, mainly in the cells lining the bronchus of the lungs. But those mutagens can also circulate through the body and produce an elevated mutational load elsewhere, such as the bladder, and contribute to tumours at those sites.

Because each mutational process leaves a unique ‘signature’ – pattern of damage in the genome – scientists can now read the genome of a cell and work out what it has been exposed to. In the last 10 years, work at the Sanger Institute has uncovered over 100 different mutational signatures, shedding light on the diverse processes that generate somatic mutations in our bodies.

Cancer

The role of somatic mutations is predominantly studied in relation to cancer. Although most mutations in a cancer cell are harmless ‘passengers’, a small number act as ‘drivers’, which give the cell an advantage to grow. Over decades, these drivers allow a rogue clone of cells to evolve into cancer.

Researchers including those at Sanger have harnessed genomic technologies to sequence tens of thousands of cancer genomes, revealing around 500 to 1,000 genes that can drive cancer when mutated. This knowledge underpins precision treatments and is reshaping our understanding of cancer risk.

In addition, work led by Group Leader, Dr Jyoti Nangalia, and international collaborators, is exploring the mechanisms by which our cells avoid cancer. The research, also known as the Cancer Avoidance Project, will sequence thousands of samples to identify mutations that help cells avoid cancer by protecting healthy cells and eliminating harmful ones. By understanding how these ‘protective’ mutations work, the researchers hope to develop treatments that mimic their effects and stop cells from progressing towards cancer.

Normal tissue

Until recently, our understanding of somatic mutations in normal tissue was limited. Now, with technological advances, we have developed a much better idea of what the landscape of somatic mutations looks like in normal cells. One of the biggest surprises so far from recent research is just how common driver mutations are in healthy tissue. In parts of the skin and oesophagus, up to 80 per cent of cells in older adults carry at least one cancer-associated driver mutation – yet under the microscope the tissue looks completely normal.^1,2 This work led by Senior Group Leader, Dr Phil Jones, has revealed that most mutated clones simply never become cancer. A major focus of research in Phil’s group is the use of genomic tools, including gene editing and single-cell analysis, to understand mutations in normal tissues, how mutant cell clones compete with one another and the earliest stages of tumour development from normal tissue.

So far, this work has revealed that the body is full of ‘silent’ evolutionary battles between cell clones and very few mutations, even driver mutations, actually lead to disease. In fact, cancer is actually a rare outcome of a much broader, mostly harmless process.

Other diseases

Another area of research that is emerging – and a focus here at the Institute – is understanding how somatic mutations contribute to diseases other than cancer. This is both in the sense of it causing other diseases but also protecting cells from disease.

For example, work led by Dr Peter Campbell, former Head of the Cancer, Ageing and Somatic Mutation programme – now called Somatic Genomics – found mutated clones that appeared to protect cells from the toxic effects of fat accumulation in metabolic liver disease.³ These mutations provided cells with a survival advantage, helping them thrive under stress. Understanding these protective mutations could lead to new therapies that mimic their effects.

In addition, it has long been hypothesised that mutations accumulating over life drive ageing. Research from groups led by Senior Group Leader, Professor Mike Stratton, Group Leader, Dr Iñigo Martincorena, and Peter has provided new insights into this hypothesis.^4–6 Ongoing work at the Sanger Institute is now focussed on understanding the precise role that somatic mutations may play in various age-related diseases.

For decades, efforts to study somatic mutations – especially in normal tissues – were limited by the constraints of available technologies. Methods such as whole-genome sequencing, targeted panels (sequencing of selected cancer-relevant genes) and single-cell sequencing transformed our understanding of somatic mutations in cancer cells, revealing driver mutations, clonal architectures (the makeup of distinct genetic cell populations) and the evolutionary trajectories of tumours. However, these powerful tools lacked the accuracy needed to reliably detect the rarest mutations, whether in cancerous or healthy tissues. To overcome this barrier, Iñigo and his team recently developed NanoSeq – an ultra-accurate single-molecule sequencing method that pushes the boundaries of detection.⁷ This newly-refined technology enables researchers to identify extremely rare somatic mutations with unprecedented precision across both cancerous and normal tissues.

Somatic mutations in a way are beautiful as they preserve the story of how our cells change and challenge the things we encounter throughout life. While some of these changes are harmless, others can have profound effects on our health. As genomic technologies have become faster and more affordable, researchers are now able to map somatic mutations across the entire body and across populations worldwide. This is revealing early driver mutations that can open the doors to better diagnosis and personalised treatments. These mutations also act as footprints of environmental exposures, helping us understand disease risk and inform preventive measures.

Beyond cancer, somatic mutations are emerging as new players in a range of other diseases – developmental, neurological and autoimmune – offering new diagnostic and therapeutic avenues. Alongside this, insights into somatic mutations can allow us to explore how we can harness our natural defence mechanisms to identify how to protect cells from different diseases. By studying how mutations accumulate over our lifetime, we can also gain deeper insight into tissue maintenance and ageing.

Somatic mutations can also provide insight into germline cells (sperm and egg). Understanding somatic mutational processes is key as many of the cellular pathways that generate mutations are shared between germline and somatic cells. The key difference is that the germline has evolved ways to keep mutation accumulation to an absolute minimum compared to somatic cells. Understanding how and why that happens is something Group Leader, Dr Raheleh Rahbari’s team is interested in. The researchers recently observed that as men age, certain sperm mutations gain a growth advantage, increasing the risk of passing harmful genes to children.⁸ This process, which acts like a hidden form of evolution in the male germline, was found to predominantly affect genes associated with developmental disorders and some cancers.

Over the next decade, research on somatic mutations in normal cells is expected to transform our understanding of disease and ageing, revealing how mutational landscapes change across the lifespan and in different conditions. Identifying genes that enable mutated cells to survive stress could provide new therapeutic targets across many diseases. Simultaneously, mapping exogenous exposures that increase mutation rates could enable disease prevention, for example, by reducing cancer risk linked to environmental factors.

One area that is of particular interest at the Institute is the link between early onset colorectal cancer and the microbiome. By understanding where mutagenic chemicals produced by gut bacteria may drive mutations, we could open opportunities in the future to prevent disease by managing the microbiome.

In addition, Mike and Raheleh’s groups are collaborating on their second PanBody project. This work will analyse DNA changes that accumulate in cells across around 50 different tissue types, studying samples from people of different ages. By comparing tissues from many individuals, the researchers aim to reveal how mutation levels vary between tissues and cell types, and to understand the biological processes driving these changes. They will do this by examining distinctive mutational signatures left behind by different DNA-damaging processes. Building directly on a previous collaborative study published a few years ago,⁹ this project aims to greatly expand our understanding of how DNA changes build up in the human body over a lifetime and how they contribute to disease risk.

Despite the huge progress in somatic mutation research, many questions remain. What biological processes cause the most common mutations? Why do some mutated clones become cancerous while others do not? And can the natural processes happening in our tissues every day be used to improve human health?

What is clear is that somatic mutations are far more than genetic errors: they are the stories our cells write as we live our lives.