NEW YORK (GenomeWeb) – A study in the journal Cancer Prevention Research has started characterizing the somatic mutations that occur in colorectal adenomas, or polyps, prior to colorectal cancer development.
Researchers from the University of Texas MD Anderson Cancer Center and elsewhere used exome sequencing to profile mutations in colorectal adenomas from a dozen individuals with familial adenomatous polyposis, a condition that predisposes individuals to colorectal cancer. Together with SNP data from 14 more familial adenomatous polyposis patients, the sequence data revealed recurrent mutations affecting some of the same genes implicated in colorectal cancer itself, albeit at lower rates of mutation.
"Our study provides researchers with a catalogue of genomic changes that precede the development of colorectal cancer in patients with [familial adenomatous polyposis]," senior author Eduardo Vilar, a clinical cancer prevention researcher at MD Anderson Cancer Center, said in a statement. "This identifies numerous molecules to investigate as potential targets for colorectal cancer prevention therapeutics."
Vilar and his colleagues used Illumina HiSeq 2000 instruments to sequence protein-coding regions in the genome from 25 adenomas — also known as adenomatous polyps — in 12 individuals with familial adenomatous polyposis, along with matched normal blood samples. For 10 of the patients, they also did exome sequencing on samples of intestinal mucosa adjacent to the adenomas.
The team found that the majority of the adenoma samples profiled contained mutations affecting components of the WNT signaling pathway. Like colorectal tumor samples, several adenomas appeared to be multi-clonal. The adenomas also contained recurrent changes to driver genes such as APC, KRAS, FBXW7, and TCF7L2, and were prone to cytosine-to-thymine DNA base substitutions.
The team's exome sequence data suggested that sites on chromosome 5, 7, and 13 were prone to allelic imbalance in the adenomas, resembling patterns found in stage I colorectal carcinomas. Similar chromosomal alterations turned up when the group tested another 37 adenomas and matched normal samples from 14 other individuals with familial adenomatous polyposis for allelic imbalance using SNP array data.
While the mutation rates in adenomas remained far lower than those described in colorectal cancer tumors — coming in at 83 mutations in each adenoma sampled, on average — the researchers found enhanced somatic mutations with increasing patient age.
And at least some of the at-risk, but adenoma-free, samples seemed to be susceptible to somatic mutations as well, with mutation rates in the adenoma-adjacent samples also rising with age.
The study "provides a much better understanding of the sequence of genetic events in colorectal cancer pre-malignancy," Vilar said. "The genomic profiles of at-risk mucosa and adenomas illustrate the evolution from normal tissue to carcinoma via greater resolution of molecular changes at the inflection point of premalignant lesions," he and his colleagues wrote.
The team is reportedly planning similar studies of mutations in colorectal adenomas from individuals without familial adenomatous polyposis, in the hopes of further untangling somatic mutations that prompt cancer formation.