Research teams led by UK scientists have sequenced the entire genome of two deadly cancers, malignant melanoma and lung cancer, revealing for the first time almost all of the tens of thousands of mutations in the DNA of cancer cells that occur during a person’s lifetime.

The research was led by scientists from the Wellcome Trust Sanger Institute at Hinxton in Cambridge, and appears as two studies published online in advance in the 16 December issue of Nature.

Cancer is driven by mutation, some of which is driven by lifestyle: these studies help to show how much.

For instance, take tobacco smoking: worldwide it is the main lifestyle-related cause of cancer because over 60 chemicals in tobacco smoke are known to bind to and mutate the DNA in our cells.

About one million people worldwide die from lung cancer every year, and almost all cases are linked to smoking.

The researchers found nearly 23,000 mutations in lung cancer cells, suggesting that for each packet of cigarettes, a typical smoker acquires one mutation in his or her DNA.

In the lung cancer genome study the researchers used a small-cell lung cancer cell line from one person, and in the melanoma genome study they used a malignant melanoma and a lymphoblastoid cell line from another person.

The melanoma genome showed even more mutations: over 30,000 in all, giving a record of how and when the patient acquired them.

Although malignant melanoma only accounts for 3 per cent of skin cancers, it causes 75 per cent of skin cancer deaths.

Professor Mike Stratton, from the Cancer Genome Project at the Wellcome Trust Sanger Institute, and co-author of both studies, told the press that:

“These are the two main cancers in the developed world for which we know the primary exposure.”

“For lung cancer, it is cigarette smoke and for malignant melanoma it is exposure to sunlight,” he added, explaining that:

“With these genome sequences, we have been able to explore deep into the past of each tumour, uncovering with remarkable clarity the imprints of these environmental mutagens on DNA, which occurred years before the tumour became apparent.”

In a rather poignant observation, Stratton described how he and his team could also see:

“The desperate attempts of our genome to defend itself against the damage wreaked by the chemicals in cigarette smoke or the damage from ultraviolet radiation.”

“Our cells fight back furiously to repair the damage, but frequently lose that fight,” he added.

For the two studies, Stratton and colleagues used powerful new DNA sequencing technologies to decode completely the genome of both tumour tissue and normal tissue.

They then compared the genome sequences of each of the cancers to that of the corresponding healthy tissue and picked out the cancer-specific changes.

A press statement from the Wellcome Trust said these studies are:

“The first to produce comprehensive genome-wide descriptions of all classes of mutation, producing rich accounts of the genetic changes in the development of the two cancers.”

Dr Andy Futreal of the Wellcome Trust Sanger Institute, and another co-author of both studies, said:

“In the melanoma sample, we can see sunlight’s signature writ large in the genome.”

But he said because they had sequenced what were essentially complete catalogues of the mutations in both cancers, they could also see other “more mysterious processes acting on the DNA”, including what they suspect to be the mutations that actually drive the cells to become cancerous.

We already know that only some mutations found in cancer actually promote cancer growth, the others are often described as “passengers”.

Tracking down the mutations that drive cancer will be their major challenge for the next few years, said Futreal.

Dr Peter Campbell, who also co-authored both studies and is also from the Wellcome Trust Sanger Institute, said we have spent the last 10 years reaping the benefits of sequencing the entire human genome, and there is still a lot of work to do on cancer genomes, but:

“The knowledge we extract over the next few years will have major implications for treatment.”

“By identifying all the cancer genes we will be able to develop new drugs that target the specific mutated genes and work out which patients will benefit from these novel treatments,” said Campbell.

The idea is that it will one day it will not only be possible but also cost-effective to map the entire genome of a each cancer patient and thus select and direct treatments specifically for the individual patient.

The research behind these two studies is part of the International Cancer Genome Consortium, whose ultimate goal is to sequence the genomes of over 100 different types of cancer, using the model of the Human Genome project to coordinate cancer genome sequencing across the globe.

Eventually this will lead to a catalogue of mutations across the wide and diverse range of cancer types, and give researchers, practitioners, all of us, better ways of understanding, preventing, detecting and treating cancer.

“A small-cell lung cancer genome with complex signatures of tobacco exposure.”
Erin D. Pleasance, Philip J. Stephens, Sarah O’Meara, David J. McBride, Alison Meynert, David Jones, Meng-Lay Lin, David Beare, King Wai Lau, Chris Greenman, Ignacio Varela, Serena Nik-Zainal, Helen R. Davies, Gonzalo R. Ordoñez, Laura J. Mudie, Calli Latimer, Sarah Edkins, Lucy Stebbings, Lina Chen, Mingming Jia, Catherine Leroy, John Marshall, Andrew Menzies, Adam Butler, Jon W. Teague, Jonathon Mangion, Yongming A. Sun, Stephen F. McLaughlin, Heather E. Peckham, Eric F. Tsung, Gina L. Costa, Clarence C. Lee, John D. Minna, Adi Gazdar, Ewan Birney, Michael D. Rhodes, Kevin J. McKernan, Michael R. Stratton, P. Andrew Futreal & Peter J. Campbell.
Nature, Advanced online publication, 16 Dec 09.

“A comprehensive catalogue of somatic mutations from a human cancer genome.”
Erin D. Pleasance, R. Keira Cheetham, Philip J. Stephens, David J. McBride, Sean J. Humphray, Chris D. Greenman, Ignacio Varela, Meng-Lay Lin, Gonzalo R. Ordóñez, Graham R. Bignell, Kai Ye, Julie Alipaz, Markus J. Bauer, David Beare, Adam Butler, Richard J. Carter, Lina Chen, Anthony J. Cox, Sarah Edkins, Paula I. Kokko-Gonzales, Niall A. Gormley, Russell J. Grocock, Christian D. Haudenschild, Matthew M. Hims, Terena James, Mingming Jia, Zoya Kingsbury, Catherine Leroy, John Marshall, Andrew Menzies, Laura J. Mudie, Zemin Ning, Tom Royce, Ole B. Schulz-Trieglaff, Anastassia Spiridou, Lucy A. Stebbings, Lukasz Szajkowski, Jon Teague, David Williamson, Lynda Chin, Mark T. Ross, Peter J. Campbell, David R. Bentley, P. Andrew Futreal & Michael R. Stratton.
Nature, Advanced online publication, 16 Dec 09.

Source: Wellcome Trust.

Written by: Catharine Paddock, PhD