Uncovering the origins of cancer in healthy skin

Thursday, 2 July 2015

(Written by Iñigo Martincorena, Cancer Genome Project, Wellcome Trust Sanger Institute Cambridge, UK) 

In the year 2001, the sequence of the human genome was announced as a milestone in science history. This represented a nearly complete map of the common genetic information in all of us. The project had taken over 10 years, the work of thousands of scientists around the globe, and it had cost approximately 3,000 million euros. This huge effort marked the beginning of a genomic revolution in biology.

Although it provided an unprecedented wealth of information, a single reference sequence for all humans contained little information on what makes each of us different or on the basis of genetic diseases. Since then, however, sequencing technologies have evolved dramatically. Nowadays, a person can be sequenced in a few days for less than 1,000 euros, and the cost continues to drop rapidly. This has allowed us to go from a single reference human genome to sequencing many thousands of people, unravelling the basis of many diseases and bringing us much closer to an era of personalised genomics in the clinic.

A field that has benefited enormously from the boom of sequencing technologies is cancer research. Cancer is largely caused by mutations that accumulate in our cells throughout life, which make every tumour unique. Genome sequencing can be used to catalogue the entire list of mutations in a cancer, providing a detailed understanding of the basis of any given tumour. The first genome of a cancer was sequenced in 2009 at the Sanger Institute (Cambridge, United Kingdom), where I work as a postdoctoral researcher. Just 6 years later, over 10,000 cancers have been sequenced throughout the world, providing a detailed catalogue of the genes altered across a wide range of cancer types. And this number is predicted to increase to several hundred thousand in the next few years. This is proving to be an invaluable resource for cancer research and, as we continue to learn how to use this vast information, it will significantly improve cancer diagnosis and therapy.

We have now learned that the genome of a cancer typically contains between 1,000 to 20,000 acquired mutations. Of these, only a handful of mutations (called driver mutations) are believed to be directly responsible for the cancer, having affected key genes that control the normal proliferation of cells. Remarkably, while we have a detailed understanding of the mutations present in many cancers, we still know very little about how normal cells begin to accumulate these mutations as they evolve into cancer.

At the Sanger Institute, we are beginning to explore the mutations present in normal tissues to better understand how cancer emerges from healthy cells. In a study that we published last month, we used new sequencing techniques to reveal for the first time the mutations present in normal skin from healthy individuals. Surprisingly, we found far more mutations that we expected to see in a normal tissue. We found that normal cells from sun-exposed skin contain many thousands mutations, even more than many tumours. The majority of these mutations were caused by ultraviolet rays from exposure to the sun. More surprisingly, we found that over a quarter of the cells in sun-exposed skin had already acquired one cancer-driver mutation and so had given a first step towards becoming a cancer. These cells formed small clones that grew slightly faster than other cells in the skin, and we found over 100 such clones in every square centimetre of sun-exposed skin. Despite this number of cancer mutations in normal skin was a big surprise, almost certainly none of these cells would have developed into skin cancer during the lifetime of these individuals. Our bodies have very strict controls against cancer and these mutant cells were still a few steps away from being able to form a tumour. Yet, you can help your body and protect yourself against skin cancer by remembering to put on sunscreen when you step out in the sun this summer.

This study of normal skin gave us an unprecedented look into the first steps that skin cells take to become cancerous. In addition to continuing sequencing cancer genomes, at the Sanger Institute we now plan to extend this work on normal cells into other organs. Understanding the frequency of cancer mutations in normal cells from different parts of the body and in different people would help us better understand how cancer emerges, and perhaps identify ways to detect cancer early or prevent it.

The potential of genome sequencing is enormous but it is still mainly restricted to research institutions. However, with the rapidly lowering cost of the technology and the constant development of new applications, we should expect genome sequencing to be adopted by hospitals within the next few years. The revolution of genomics offers exciting opportunities for patients, hospitals and industry, but also poses a significant challenge to universities and students. Making sense of genomic data requires a good background in biology, computer programming and statistics, still an uncommon mix in most biology or medical degrees. Yet, such mixed training should be actively promoted in universities to take full advantage of the many opportunities that lie ahead in the genomic revolution.

Iñigo Martincorena 
BIO & BCH '07

*Reference:Martincorena et al., 2015. High burden and pervasive positive selection of somatic mutations in normal human skin. Science. 348(6237):880-6.http://www.sciencemag.org/content/348/6237/880

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