Study provides better understanding of sequence of genetic events in colorectal cancer premalignancy

Bottom Line: Whole-exome sequencing of both colorectal adenomas (precancers often called polyps) and intestinal mucosa at risk for developing into adenomas from patients with familial adenomatous polyposis (FAP) has generated a comprehensive picture of the genomic alterations that characterize the evolution of normal mucosa to precancer.

Journal in Which the Study was Published: Cancer Prevention Research, a journal of the American Association for Cancer Research.

Senior Authors: Eduardo Vilar, MD, PhD, assistant professor in the Department of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center in Houston, and Paul Scheet, PhD, associate professor in the Department of Epidemiology at The University of Texas MD Anderson Cancer Center.

Background: Colorectal cancers develop from adenomas as a result of the sequential acquisition of genomic alterations, according to Vilar. We have a comprehensive view of the genomic alterations of colorectal cancers, thanks to projects like The Cancer Genome Atlas (TCGA), but far less is known about the order in which these genomic alterations accumulate because the genomic landscapes of adenomas and at-risk mucosa have been challenging to characterize, he explained.

How the Study Was Conducted and Results: Vilar, Scheet, and colleagues used whole-exome sequencing to analyze 25 adenomas, 10 samples of mucosa adjacent to adenomas (at-risk mucosa), and 12 blood samples from 12 patients with FAP.

The researchers identified a total of 2,314 different genomic alterations in the adenomas and 279 different genomic alterations in the at-risk mucosa. Among these genomic alterations, 2,067 and 268, respectively, were somatic mutations, which are changes to single bases (the units that make up DNA). The mean somatic mutation frequency was 83 per adenoma and 27 per sample of at-risk mucosa, resulting in mean mutation rates of 1.75 and 0.49 per megabase of DNA, respectively.

Analysis of whole-exome sequencing data from 107 colorectal cancers in the TCGA showed that colorectal cancers had higher mean mutation rates than adenomas. One subtype had a mean mutation rate of 4.26 per megabase of DNA and another subtype a mean mutation rate of 50.88 per megabase of DNA.

Many of the genomic alterations in the adenomas were in genes known to have a role in fueling cancer, and according to Vilar, the research team has estimated from its data that almost 25 percent of the somatic mutations in adenomas are already present in the at-risk mucosa.

Author Comment: "Our study provides researchers with a catalog of genomic changes that precede the development of colorectal cancer in patients with FAP, a genetic condition in which patients have a 100 percent chance of developing colorectal cancer at some point very early in their life," said Vilar. "This identifies numerous molecules to investigate as potential targets for colorectal cancer prevention therapeutics. Such chemopreventive agents could benefit not just patients with familial adenomatous polyposis, but also adults who have had polyps removed and those at high risk for colorectal cancer who decline screening.

"Our information provides a much better understanding of the sequence of genetic events in colorectal cancer premalignancy," Vilar added. "This is an important step because there is interest in the cancer prevention community in developing a 'Pre-Cancer Genome Atlas' that mirrors the information for invasive cancers that is in the TCGA."

Limitations: According to Vilar, the two main limitations to the study are that the adenomas analyzed were all from patients with FAP and that there is not 100 percent certainty that the adenomas analyzed would have gone on to become invasive cancers. To address these two issues, Vilar said that the research team is planning on analyzing adenomas from individuals who do not have FAP (that is, the general population) and the adenoma component from colorectal cancers that have already been resected.

Source:

American Association for Cancer Research

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