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Colorectal Cancer Clues Provided by Polyp Profiles

NEW YORK (GenomeWeb) – A Mayo Clinic-led team has uncovered mutation, methylation, expression, and copy number profiles that seem to distinguish colorectal cancer-adjacent polyps from colorectal polyps in cancer-free individuals.

The researchers used a combination of whole-genome sequencing, RNA sequencing, and reduced-representation bisulfite sequencing (RRBS) to profile cancer-adjacent or cancer-free colorectal adenomatous polyp samples from dozens of individuals with or without colorectal cancer. The results, appearing in Scientific Reports today, pointed to alterations that occurred in both cancer-adjacent polyps (CAPs) and cancer-free polyps (CFPs), as well as molecular profiles with promise for differentiating CAPs from CFPs.

"These findings provide a resource of molecular distinctions between polyps with and without cancer, which have the potential to enhance the diagnosis, risk assessment, and management of polyps," senior author Lisa Boardman, a gastroenterology and hepatology researcher at the Mayo Clinic, Rochester, and her colleagues wrote.

Though it is well recognized that benign adenomatous polyps are prone to progress to colorectal carcinoma (CRC) over time, the team explained, there are still unanswered questions about the specific mutations, expression changes, and epigenetic shifts that determine whether a polyp will remain harmless or morph into cancer.

"The identification of the molecular profiles that differentiate CAPs from CFPs has the potential to lead to tailored colonoscopy surveillance intervals," the authors noted. "Adding defined molecular features to assess a polyp's risk for malignancy will improve the impact of surveillance on CRC prevention."

The analysis focused on 90 samples collected over more than a decade at the Mayo Clinic from 31 individuals with cancer-free lesions or with polyps that had advanced to colorectal carcinomas. They noted that the CAP tissues taken from CRC-neighboring sites from 16 CAP cases included "tissues from the residual polyp of origin and contiguous cancer." On the other hand, the CFPs came from 15 individuals with lesions that had not progressed to cancer.

Using Illumina HiSeq X instruments, collaborators at the Broad Institute did whole-genome sequencing on all of the available polyp samples, generating 30-fold average genome coverage of these samples. They also did RNA-seq and RRBS paired-end sequencing on 69 and 76 samples, respectively, with Illumina HiSeq 2000 and/or 2500 instruments.

Along with a significant uptick in somatic mutations, the team noted that CAPs showed altered expression of genes such as GREM1 or IGF2 and a sharp rise in methylation in many portions of the genome, relative to the CFP. And while genes such as APC, KRAS, and BRAF were significantly mutated in cancer-free and cancer-adjacent polyps, other genes appeared to have CAP-specific mutations — a set that included TP53, SMAD2/4, and PIK3CA.

The researchers' integrative analyses, bringing together molecular data from all three of the approaches used to characterize the samples, highlighted 124 genes with CAP-related alterations revealed by two or more molecular alteration types.

Though they cautioned that larger analyses are needed to verify and broaden the current findings, the authors noted that the "definition of molecular alterations linked with progression of polyps to cancer could lead to modifiable targets for chemoprevention or other preventative interventions, and may also serve up candidate markers for screening."

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