Lung cancer and melanoma genomes decoded
16 December 2009
Research teams led by the Wellcome Trust Sanger Institute have
achieved the first comprehensive analyses of two cancer genomes. The
Cambridge-based institute is the centre of gene sequencing in the UK.
The studies used powerful new DNA sequencing technologies to decode
completely the genome of both tumour tissue and normal tissue from a
lung cancer and a malignant melanoma (skin cancer) patient. By comparing
the genome sequence from the cancer to the genome from healthy tissue
they could pick up the changes specific to the cancer.
The 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.
All cancers are caused by mutations in the DNA of cancer cells which
are acquired during a person's lifetime. Lung cancer causes around one
million deaths worldwide each year: almost all are associated with
smoking. The number of mutations found suggest that a typical smoker
would acquire one mutation for every 15 cigarettes smoked.
Although malignant melanoma comprises only 3% of skin cancer cases,
it is the cause of three out of four skin cancer deaths. The melanoma
genome contained more than 30,000 mutations that carried a record of how
and when they occurred during the patient's life.
"These are the two main cancers in the developed world for which we
know the primary exposure," explains Professor Mike Stratton, from the
Cancer Genome Project at the Wellcome Trust Sanger Institute. "For lung
cancer, it is cigarette smoke and for malignant melanoma it is exposure
to sunlight. 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.
"We can 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."
"In the melanoma sample, we can see sunlight's signature writ large
in the genome," says Dr Andy Futreal, from the Wellcome Trust Sanger
Institute. "However, with both samples, because we have produced
essentially complete catalogues, we can see other, more mysterious
processes acting on the DNA. Indeed, somewhere amongst the mutations we
have found lurk those that drive the cells to become cancerous. Tracking
them down will be our major challenge for the next few years."
The lung cancer genome contained more than 23,000 mutations, the
melanoma more than 33,000. Identifying the causative mutations among the
large number found poses a challenge, but the complete genome sequences
mean, that for the first time, that challenge can be met.
"Nearly ten years on, we are still reaping the benefit from the first
human genome sequence and we have much still to do to get to grips with
these new disrupted landscapes of cancer genomes," explains Dr Peter
Campbell from the Wellcome Trust Sanger Institute. "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."
A complete genome catalogue for each patient would be expected to
help select between treatments and to direct treatment in the most
efficient and cost-effective way. The Sanger Institute is already
working with researchers at Massachusetts General Hospital on a large
scale project to tie genetic changes in cancers to their responses to
"We want to drive healthcare through better understanding of the
biology of disease," says Sir Mark Walport, Director of the Wellcome
Trust. "Previous outcomes from our Cancer Genome Project are already
being fed into clinical trials, and these remarkable new studies further
emphasise the extraordinary scientific insights and benefits for
patients that accrue from studying the genome of cancer cells.
"This is the first glimpse of the future of cancer medicine, not only
in the laboratory, but eventually in the clinic. The findings from today
will feed into knowledge, methods and practice in patient care."
The human genome is large. Moreover, there are more than one hundred
different types of cancer and sequencing genomes is expensive. To ensure
that thousands of cancers ultimately are sequenced in the same way as
these two, the International Cancer Genome Consortium has been
established, on the model of the Human Genome project itself to
coordinate cancer genome sequencing across the globe.
These catalogues of mutations across the broad diversity of cancer
types will provide powerful insights into the biology of cancer and will
be the foundation for understanding cancer causation and improving
prevention, detection and treatment.
Lung cancer genome mutations — one a day for smokers
Research published in Nature shows that the genome of a lung
cancer patient has more than 20,000 mutations: this total implies that a
typical smoker would acquire one mutation for every 15 cigarettes
smoked. The cancer genome is ravaged by mutations, many of which are
repaired as the genome tries to defend itself.
In many cases, that battle is lost and some of the many thousands of
mutations hit key genes and lead to cancer.
In the study, the researchers compared the genomes in normal blood
cells and tumour cells from a patient with small cell lung cancer
(SCLC). They sequenced the genome a total of 60 times over to develop a
comprehensive catalogue of all known types of DNA mutation.
"For the first time, we have a comprehensive map of all mutations in
a cancer cell," said Dr Peter Campbell, senior author on the work, from
the Cancer Genome Project at the Wellcome Trust Sanger Institute, "The
profile of mutations we observed is exactly that expected from tobacco,
suggesting that the majority of the 23,000 we found are caused by the
cocktail of chemicals found in cigarettes. On the basis of average
estimates, we can say that one mutation is fixed in the genome for every
15 cigarettes smoked."
The mutations range from single-letter changes in the code to
deletions or rearrangements of hundreds of thousand of letters. Most are
‘passenger' mutations, previously defined by the team as mutations that
do not influence the development of the cancer, but are a consequence of
the highly mutagenic environment in many cancer cells.
"Cancers occur when control of cell behaviour is lost - cells grow
how, when and where they shouldn't," explains Dr Andy Futreal from the
Wellcome Trust Sanger Institute. "Mutations in DNA caused by, for
example, cigarette smoke are passed on to every subsequent generation of
daughter cells, a permanent record of the damage done. Like an
archaeologist, we can begin to reconstruct the history of the cancer
clone - revealing a record of past exposure and accumulated damage in
The study was so comprehensive that the team could see signatures of
an undiscovered system of DNA repair, reducing the mutations in highly
active genes, suggesting the genome seeks to preserve these regions
above many others.
However, as previous studies suggested, there was not one mutation
that stood out as ‘the lung cancer gene'. One gene - CHD7 - was found to
be mutated in several SCLC samples. This gene is part of an emerging
pattern that cancers often contain mutations in genes that are
generalists in regulating genetic activity alongside more specific
This work and the companion study on malignant melanoma using
massively parallel sequencing portend an era in which the forces of
mutagens shaping our genome can be described and the consequences of
these processes can be decoded.
It is clear that rates of lung cancer fall to around normal some 15
years after quitting smoking: the suspicion is that lung cells
containing mutations are replaced by new cells derived from lung stem
cells that are clear of mutation.
"This is a difficult disease to diagnose and treat," continues
Professor Stratton, "but fortunately we do know how people can minimize
their risk of lung cancer. Even current smokers substantially reduce
their risk by giving up now - the more time passes off tobacco, the more
the risk decreases."
Mutations of malignant melanoma genome
In a landmark study, researchers have described the first
comprehensive catalogue of somatic mutations in a cancer genome. The
breadth and clarity of the view of the genome from a patient with
malignant melanoma is matched only by a companion study on lung cancer,
published in the same issue of Nature.
The melanoma genome contains more than 33,000 mutations, many of
which bear the imprint of the most common cause of melanoma — exposure
to ultraviolet (UV) light. But the comprehensive catalogue of mutation
reveals other more unusual mutations and many not related to exposure to
Malignant melanoma is responsible for three out of four skin cancer
deaths: most forms of skin cancer are relatively treatable, especially
if detected early.
"This is an unprecedented view of a cancer genome," says Professor
Michael Stratton, from the Cancer Genome Project at the Wellcome Trust
Sanger Institute. "Written within this code is the history of this
cancer - its mutations from UV light and the mutations it acquired when
it spread within the patient. We have revealed the archaeology of
exposure in this cancer genome, which becomes a palimpsest of successive
"It is amazing what you can see in these genomes," comments Dr Peter
Campbell from the Wellcome Trust Sanger Institute. "UV-light-induced
mutations leave a typical signature, forming the vast majority of the
"Indeed because of the clarity of the genome data, we can distinguish
some of the early, UV-induced mutations from the later mutations that do
not have this signature, presumably occurring after the cancer cells
spread from the skin to deeper tissues.
The sequence also shows the genome's attempts to protect itself from
damage, with DNA repair systems most active in gene regions, whereas the
regions between genes are left less well guarded. Even with these
actions, 182 changes in genes that would impair their function were
"Within the lists of disrupted genes are all those that have driven
the original cell to this malignant state," comments Dr Andy Futreal,
from the Cancer Genome Project at the Wellcome Trust Sanger Institute.
"We know that this cancer sample has a mutation in BRAF and other genes
already implicated in melanoma. To discern all the important changes, we
will need to analyse more samples."
The genomes - cancer cell and normal cell - were sequenced more than
70 times over to produce accurate data.
The project was led by researchers from the Wellcome Trust Sanger
Institute. In 2002, this group discovered that a mutation in one gene
called BRAF was important in driving development of melanoma. That
discovery has already driven the development of novel therapies that are
in clinical trials.
1. Pleasance ED et al. (2009) A small-cell lung cancer
genome with complex signatures of tobacco exposure. Nature
2. Pleasance ED, Cheetham RK et al. (2009) A comprehensive
catalogue of somatic mutations from a human cancer genome. Nature