Colorectal Cancer Coverage from Every Angle

Genomic Sequencing of Colorectal Cells Sheds Light on Earliest Stages of Cancer

By: Sarah Campen, PharmD
Posted: Wednesday, November 20, 2019

A team of researchers has characterized all of the classes of somatic mutation in hundreds of normal colorectal epithelial cells, revealing the earliest stages of colorectal carcinogenesis. By developing technology to sequence the genomes of small numbers of colorectal cells, Michael R. Stratton, MBBS, PhD, of the Wellcome Sanger Institute in Hinxton, United Kingdom, and colleagues were able to study genetic mutations in remarkable detail. Their findings were published in Nature.

“There is a whole landscape of genetic mutations in our cells that we haven’t previously appreciated,” stated study coauthor Henry Lee-Six, of Wellcome Sanger, in an institutional press release. “We’ve shown that these mutant cells are abundant, though the vast majority don’t go on to cause cancer.”

Using laser capture microscopy, the researchers removed 2,035 individual colorectal crypts from the samples of 42 individuals, ranging from 11 to 78 years of age. Each crypt contained approximately 2,000 cells derived from one single ancestral stem cell; they were analyzed individually using whole-genome sequencing.

The research team identified signatures of multiple mutational processes, including six new signatures not previously described. Some signatures were ubiquitous and continuous, whereas others were present in only a few individuals, in some crypts, or during certain periods of life. Probable driver mutations were present in about 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are “rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.”

Of interest, one individual who had undergone chemotherapy had five times the age-standard mutational load in all colorectal cells—and potentially many other tissues. The researchers noted that this observation “provides new insight into the effect of such exposures and raises questions pertaining to the relationship between mutational load and the relatively modest effect of chemotherapy on cancer risk.”

Disclosure: The study authors reported no conflicts of interest.

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