New Genetic Sequencing Technology Bolsters Colon Cancer Research

Researchers from the Wellcome Sanger Institute and colleagues have recently created technology that can sequence colon cell genomes with unprecedented precision. This technique allowed the scientists to find complex patterns of mutations, including those in cancer genes, and a large variability of mutations occurring within and between individuals. This work will help researchers understand how healthy cells become cancerous, furthering their understanding of early colon cancer. These findings were published on October 23 in the journal Nature.

With 42,000 new cases of colon cancer each year in the UK, the disease ranks as the second most common cause of cancer fatality in the nation. Genes linked to cancer, known as oncogenes, can significantly contribute to the disease’s progression if they contain specific mutations. With enough mutations in specific oncogenes, a cell can transform from being healthy to cancerous. This transition is marked by the uncontrolled proliferation of the cell, leading to tumor formation.

These mutations linked to cancer have been extensively researched in cancerous tissue over the last 40 years, but it has not been possible to do so in healthy tissue using existing technology. Studying these genetic aspects of healthy cells is essential in understanding the early stages of cancer progression.

A New Approach

In this new study, researchers developed a technique to characterize and analyze genome sequences of healthy colon cells. They were able to find cells in the earliest stages of colon cancer development, with these identified cells being morphologically normal but having unique mutations in cancer-linked genes.

“There is a whole landscape of genetic mutations in our cells that we haven’t previously appreciated – we’re walking around full of typos,” said first author Henry Lee-Six. “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 find these mutations, the researchers used a technique called laser capture microscopy to create small cavities in donor colon tissue samples that model the natural crypts of the colon. Each cell in a crypt has the same genetic mutations. In total, the scientists studied 2,035 crypts from 42 people aged 11 to 78 years.

Sanger Institute’s Sequencing Research and Development team created a novel workflow for sequencing the genomes of these laser-captured crypts. This process was fully automated, allowing for a large number of genomes to be sequenced rapidly.

“Our goal was to find a way to sequence the genomes of just a few hundred crypt cells taken from a microscope slide,” said Peter Ellis, Senior Staff Scientist at the Wellcome Sanger Institute. “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 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,” explained lead author Sir Mike Stratton, Director of the Wellcome Sanger Institute. “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.”