Polyp Mutations May Hold Key to CRC Prevention

Eduardo Vilar-Sanchez, MD, PhD

Precancerous colon polyps exhibit many of the same driver mutations that fuel the development of colorectal cancer (CRC), according to results of a study published in Cancer Prevention Research.

Identifying and better understanding these polyp mutations could aid in the development of targeted therapies and interventions for CRC prevention, said co-senior author of the study Eduardo Vilar-Sanchez, MD, PhD, an assistant professor of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center.

“In comparing polyp mutations with tumors, we have found that although polyps have a lower number of mutations compared to stage I cancer, there is already a fair amount of genomic variation accumulated in this premalignant lesion that is not yet cancerous,” said Vilar-Sanchez in an interview with OncLive. “Researchers have always been interested in understanding genomic changes in tumors, which have a significant benefit, but we believe we need to concentrate on understanding better the genetic makeup of premalignant lesions so we can come up with targeted strategies to develop preventative agents.”

With the use of advanced genetic sequencing techniques, researchers characterized genetic changes on 25 colorectal polyps, 10 adjacent mucosa, and 12 blood samples from 12 patients with familial adenomatous polyposis (FAP), a hereditary cancer syndrome caused by an inherited mutation in the APC gene. APC mutations are responsible for 80% of CRC cases, making FAP an attractive model to study CRC development, explained Vilar-Sanchez.

Researchers identified 2314 genetic changes in polyps, with an average of 83 mutations per polyp and an average rate of 1.75 mutations per megabase, or 1 million DNA bases. In adjacent mucosa, the researchers discovered 279 alterations, with an average of 27 mutations per sample and an average rate of 0.49 mutations per megabase.

The polyps showed recurrent alterations in known cancer driver genes APC, KRAS, FBXW7, TCF7L2, and allelic imbalances in chromosomes 5, 7, and 13. Eighty percent of the polyps had somatic alterations in Wnt pathway genes. Virtually, all cases of CRC result from initial dysregulation of the Wnt signaling pathway, usually as a result of mutations in the APC gene.

This link between the Wnt pathway and polyps was somewhat expected, but is still significant, said Vilar-Sanchez.

“One of the challenges is that we are just starting to develop different strategies to target the Wnt pathway for the treatment of colon cancer,” he said. “Basically, these findings are telling us that there are not many more pathways other than the Wnt pathway that are deregulated at a very early stage in the development of pre-malignancy. We need to concentrate our efforts toward developing targeted interventions towards this pathway.”

As part of the study, researchers also sequenced the mucosa in the normal-appearing tissue that was close to the polyps to determine if it had any mutations. It was determined that the mucosa did, in fact, appear to have already started to accumulate mutations, although they were not cancer-driven, said Vilar-Sanchez.

“These mutations are basically hiding there, waiting to have a driver that will initiate the premalignancy,” he explained. “This means that the majority of mutations that we have observed in tumors—and, in this case, in pre-malignancy—are already there before the cancer driver event starts.”

Prior to this study, whole-genome sequencing had not been previously utilized on polyps. Their relatively small size—often less than 1 centimeter—presented significant challenges with obtaining enough DNA, said Vilar-Sanchez. In addition, while polyps do consist of malignant cells, they also consist of many normal cells, making mutation detection difficult.

“This forced us to develop very sensitive biochromatic tools to detect these mutations,” said Vilar-Sanchez. “The signals of the mutations were hidden, and we successfully overcame that challenge. This is also a call for attention to other researchers working in the prevention field. Next-generation sequencing studies are feasible, even when you are dealing with relatively small lesions and relatively early-on lesions. It is possible to genotype these lesions and understand what it is going on.”

This study is just the first step in understanding genomic variation in pre-malignancies, said Vilar-Sanchez. Future research will include an analysis of larger groups of patients with an average risk of CRC and beyond FAP.

Additional analyses are planned on precancerous tissue to look for gene expression changes to complement genetic alterations, in order to better characterize the molecular subtypes of early polyps.

The end goal is to build a genomic map of polyp mutations, to help physicians predict which polyps present a higher risk, and to develop treatments to prevent them from progressing to cancer. There is potential that existing targeted agents—such as those used for hypertension—could be utilized as preventative agents in CRC, said Vilar-Sanchez.

“Right now, the general population is recommended to have a colonoscopy at age 50 for the prevention of colon cancer, but we don’t know which polyps are going to become cancer or not, so they are all removed,” he said. “However, people continue to get cancer. We need to understand which polyps are going to be more malignant and have more risk to become cancer, and which mutations we can exploit for prevention.”

Borras E, San Lucas A, Chang K, et al. Genomic landscape of colorectal mucosa and adenomas [published online May 24, 2016]. Cancer Prev Res. doi:10.1158/1940-6207.CAPR-16-0081.