Nav: Home

Uncovering the pathway to colon cancer

October 23, 2019

The hidden world of genetic changes, or mutations, in healthy colon tissue has been uncovered by scientists at the Wellcome Sanger Institute and their collaborators. The team developed technology to sequence the genomes of small numbers of colon cells, allowing them to study genetic mutations in unprecedented detail. Researchers found complex patterns of mutations, including changes in cancer genes, and a huge variability of mutations both within and between people.

The results published today (23 October 2019) in Nature, will help researchers understand how a healthy cell becomes a cancerous one, shedding light on the very earliest stages of colon cancer.

There are 42,000 new cases of colon cancer every year in the UK. Colon cancer is the second most common cause of cancer death in the UK*.

Cancer is a genetic disease, caused by genetic mutations in specific genes that can give a cell an advantage over its neighbours. With enough mutations in certain genes, a cell may become cancerous and divide uncontrollably to form a tumour.

Over the last 40 years, these cancer-driving mutations have been identified and mapped out in tumour tissue. Due to technical limitations, it has previously not been possible to identify them in healthy tissue, which is crucial to understanding the first steps towards cancer developing.

In this new study, the researchers developed methods to determine and characterise the genome sequences of healthy colon cells. The team found the very earliest stages of colon cancer development. The cells were morphologically normal, but had distinct patterns of genetic changes, including in important cancer genes.

Henry Lee-Six, first author of the research from the Wellcome Sanger Institute, said: "There is a whole landscape of genetic mutations in our cells that we haven't previously appreciated - we're walking around full of typos. We found mutations that if you saw in a cancer cell, you'd say were causing that cancer. But we found them in healthy colon tissue that looks completely normal under the microscope. We've shown that these mutant cells are abundant, though the vast majority don't go on to cause cancer."

To identify the mutations, the team used laser capture microscopy to cut out individual 'crypts', the tiny cavities which make up colon tissue, from donated samples. Each cell within a crypt has the same genetic mutations. They studied a total of 2,035 crypts from 42 people, aged 11 to 78 years.

The Sequencing Research and Development team at the Sanger Institute developed a new workflow to sequence the genomes of the laser-captured crypts. The team then fully automated the process enabling tens of thousands of genomes to be swiftly sequenced.

Dr Peter Ellis, Senior Staff Scientist at the Wellcome Sanger Institute, now working at Inivata, said: "Our goal was to find a way to sequence the genomes of just a few hundred crypt cells taken from a microscope slide. The difficulty was using such tiny amounts of DNA without introducing errors that would obscure real mutations - something that we had never done before. The method has now been used to process more than 40,000 laser capture samples. It has also been adapted for other projects where only minimal DNA is available, such as sequencing parasitic blood flukes. It's a powerful new technique."

The team also looked at mutational signatures in the genomes - tell-tale patterns, or 'fingerprints' of specific DNA changes caused by a specific chemical or process. They found signatures of multiple mutational processes in colon cells. Some had been seen before and the causes are known, including enzymes that are thought to destroy viral DNA, but in this case are damaging human DNA. Some signatures were ubiquitous and continuous, others were present in only a few individuals, in some crypts or during certain periods of life. Six signatures had never been seen before, and further research is needed to identify what causes them.

Identifying both mutational signatures and mutations in cancer driver genes in healthy cells gives a baseline picture of DNA changes in normal colon tissue. The mutations can be compared with those seen in conditions such as inflammatory bowel diseases, as well as colon cancer, to understand how and why cells evolve and change in health and disease.

Professor Sir Mike Stratton, Director of the Wellcome Sanger Institute and lead author of the research, said: "The ability to find mutations in normal cells means we can now describe how many and what types of mutations there are in different tissues across the human body, potentially providing understanding of what makes some tissues more prone to cancer than others. In this study we identified new patterns of mutations, known as 'mutational signatures', in the genomes of normal colon cells that provide clues to the causes of those mutations and thus may lead to uncovering hidden causes of colon cancer."
-end-


Wellcome Trust Sanger Institute

Related Cancer Articles:

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Making Amends
What makes a true apology? What does it mean to make amends for past mistakes? This hour, TED speakers explore how repairing the wrongs of the past is the first step toward healing for the future. Guests include historian and preservationist Brent Leggs, law professor Martha Minow, librarian Dawn Wacek, and playwright V (formerly Eve Ensler).
Now Playing: Science for the People

#566 Is Your Gut Leaking?
This week we're busting the human gut wide open with Dr. Alessio Fasano from the Center for Celiac Research and Treatment at Massachusetts General Hospital. Join host Anika Hazra for our discussion separating fact from fiction on the controversial topic of leaky gut syndrome. We cover everything from what causes a leaky gut to interpreting the results of a gut microbiome test! Related links: Center for Celiac Research and Treatment website and their YouTube channel
Now Playing: Radiolab

The Flag and the Fury
How do you actually make change in the world? For 126 years, Mississippi has had the Confederate battle flag on their state flag, and they were the last state in the nation where that emblem remained "officially" flying.  A few days ago, that flag came down. A few days before that, it coming down would have seemed impossible. We dive into the story behind this de-flagging: a journey involving a clash of histories, designs, families, and even cheerleading. This show is a collaboration with OSM Audio. Kiese Laymon's memoir Heavy is here. And the Hospitality Flag webpage is here.