Study finds early genetic changes in colorectal premalignant tissue ;
Researchers at the University of Texas MD Anderson Cancer Center have discovered mutations that can promote cancer growth early in colorectal precancerous tissue of high risk patients.
Their study, published in Cancer Prevention Research , is the first to use techniques advanced genetic sequencing to characterize the genetic changes in precancerous polyps and nearby tissue that has not been transformed into polyps. In addition to mutations in very early stages of cancer development, the results identify potential drug targets for the prevention of colorectal cancer (CRC).
Although most genetic changes present in advanced RCC are known, those occurring before cancer develops have been elusive, he explained co-Eduardo Vilar-Sanchez, MD, Ph.D. ., assistant professor, Clinical Cancer Prevention. To identify the first mutations, the researchers studied tissue and colorectal polyps or mucosa from patients with familial adenomatous polyposis (FAP), hereditary cancer syndrome caused by an inherited mutation in the APC gene.
APC mutations are responsible for 80 percent of cases of CRC, FAP making an attractive model to study the development of CRC, he explained Sanchez-Vilar. Although responsible for only 1 percent of all diagnoses, patients with FAP have a lifetime risk of 100 percent of developing CRC without preventive action.
“We have a great need to identify prevention strategies in these populations. The idea is to develop a mini atlas of premalignant genome to better understand the genomic events in small polyps early. Our study establishes a basis for identifying new biomarkers or targets for chemoprevention, “Vilar-Sanchez said.
Researchers characterized the genetic changes in polyps and adjacent mucosa samples, which, despite apparently normal considering “at risk” tissue. exome sequencing was carried out at 25 colorectal polyps , 10 adjacent mucosa, and 12 blood samples from 12 patients with PAF MD Anderson and the Catalan Institute of Oncology.
A particular challenge associated with samples of this type is that the precancerous cells with mutations of interest are mixed with most normal tissues.
“In addition to seeking Genetic mutations in a small fraction of the DNA, there is a very limited amount of total study DNA, as these are small,” said co-author Paul Scheet, Ph .D., associate professor, Epidemiology and team leader for the algorithm used for the analysis of complex sequence. “As these lesions are at a very early stage of potential transition to malignancy, evaluation of mutations requires a highly sensitive method that makes use of all available knowledge.”
The researchers identified 2,314 genetic changes in polyps, with an average of 83 mutations per polyp and an average rate of 1.75 per megabase mutations, or 1 million DNA bases. In the adjacent mucosa, the researchers found alterations 279, with an average of 27 mutations per sample and an average rate of 0.49 per megabase mutations.
Many of these mutations appeared to be in groups of genes that work together in cellular signaling networks. Members of a network called the Wnt signaling pathway, including the APC gene seems to be especially important for the transformation mucosal polyps.
“Wnt is the key driver for these types of polyps at a very early stage. It is absolutely essential for the development of premalignant colorectal cancer, and targeting Wnt should be a priority for chemoprevention,” he said Vilar-Sanchez.
By comparing mutations identified in these samples, the research team found at least 23 percent of mutations in polyps were already present in the mucosa at risk. Another comparison between polyps and cancers in stage I Cancer Genome Atlas revealed greater similarity between premalignant and cancerous tissue than expected.
“The mutation rates of adenomas were surprisingly very close to the rates of mutation found in Stage I colorectal cancer. It is obvious that see rates rise, but between polyps and cancers, there is a good degree of coincidence “said Vilar-Sánchez.
These polyps more genetic changes , similar to early stage cancers may be more likely to develop in the CRC, said Sanchez-Vilar. Unfortunately, there is no way to be sure what will transform polyps after being removed from the patient.
The study was limited by a small number of samples and the small amount of sample available. In future work, the team plans to analyze similar samples of individuals at average risk of CRC.
also plan to analyze precancerous tissue for gene expression changes to complement genetic alterations, in order to better characterize the molecular subtypes of the first polyps. Doing so can allow doctors to predict which polyps present a higher risk, and to develop treatments to prevent it from becoming cancer .
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