Sessile serrated colon polyps may be detectable noninvasively

 

Sessile serrated polyps (SSPs), notorious for being difficult to detect and for their potential to become malignant colorectal tumors, appear to be caused by a single oncogenic mutation, a finding that could lead to better early detection of some colorectal cancers through noninvasive stool testing, investigators say.

Using a comprehensive battery of genomic testing and DNA methylation profiling, David Jones, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City and his colleagues compared SSPs with familial adenomatous polyps (FAPs), and found that the V600E mutation in BRAF (V-Raf Murine Sarcoma Viral Oncogene Homolog B) was the sole cancer-causing mutation in SSPs.

They also found a distinct DNA methylation pattern unique to SSPs.

“These SSP-specific methylation patterns effectively distinguish SSP from adenomatous polyps, which could be important for both diagnosis and treatment. It also suggests that the BRAF-V600E mutation directly or indirectly results in the remodeling of the epigenome and that this may set a stage for tumor progression,” they wrote in the open-access journal PLOS One.

Approximately one-third of sporadic colorectal cancers, which account for about 95% of all colorectal malignancies, are thought to arise from premalignant serrated lesions, including SSPs, hyperplastic polyps, and traditional serrated adenomas, the authors noted.

Although SSPs and traditional serrated adenomas both have significant potential for malignant transformation, SSPs are much more common, making them important targets for research, diagnosis, and possible interventions.

“Previous surveys of cancer-associated mutations in SSP samples, through targeted analysis of limited known mutations, identified the BRAF-V600E as the key mutation in this disease. However, it is not clear whether other mutations in the same samples contribute to the etiology of this disease,” Dr. Jones and his associates wrote.

 

To better understand both the inherited (genetic) and acquired (epigenetic) basis for SSP and tumor development, the investigators used whole-exome sequencing, genome-wide mutation detection, and DNA methylation profiling on multiple samples of both SSPs and FAPs.

They performed exome sequencing on DNA extracted from SSP samples from six patients diagnosed with typical SSP-type colon polyps via colonoscopy and pathology. The samples included one each from five patients and three taken from different portions of the colon in one patient. In all of the samples, BRAF-V600E was the only common somatic mutation detected. In the patient from whom the three SSP samples were taken, the mutation was found in each polyp, but not in grossly uninvolved colon from the same patient.

The investigators next performed genome-wide DNA methylation profiling on 15 colon biopsy samples from 11 patients, including five SSPs, two traditional serrated adenomas, three FAPs, two carcinomas, one grossly uninvolved tissue sample, and two normal tissue samples. They found that the BRAF-V600E mutation correlated with a unique and reproducible DNA methylation signature.

They then determined that the DNA methylation signature that they identified is associated with specific markers for molecular characterization of SSPs, and that these markers showed an approximately 3- to 30-fold increase in methylation levels in only SSP samples.

 

Furthermore, they showed that the unique DNA methylation patterns they identified could be used to distinguish SPPs from adenomatous polyps, with better discrimination than parallel-gene expression profiling.

“The results presented here provide strong evidence that the BRAF-V600E mutation is the main cause of generation of SSP and SSP-specific DNA methylation pattern,” the investigators wrote in the study’s conclusion.

The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. The authors declared no competing financial interests in the work.

 

SOURCE: Dehghanizadeh S et al. PLOS One 13(3): e0192499.

 

Sessile serrated polyps (SSPs), notorious for being difficult to detect and for their potential to become malignant colorectal tumors, appear to be caused by a single oncogenic mutation, a finding that could lead to better early detection of some colorectal cancers through noninvasive stool testing, investigators say.

Using a comprehensive battery of genomic testing and DNA methylation profiling, David Jones, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City and his colleagues compared SSPs with familial adenomatous polyps (FAPs), and found that the V600E mutation in BRAF (V-Raf Murine Sarcoma Viral Oncogene Homolog B) was the sole cancer-causing mutation in SSPs.

They also found a distinct DNA methylation pattern unique to SSPs.

“These SSP-specific methylation patterns effectively distinguish SSP from adenomatous polyps, which could be important for both diagnosis and treatment. It also suggests that the BRAF-V600E mutation directly or indirectly results in the remodeling of the epigenome and that this may set a stage for tumor progression,” they wrote in the open-access journal PLOS One.

Approximately one-third of sporadic colorectal cancers, which account for about 95% of all colorectal malignancies, are thought to arise from premalignant serrated lesions, including SSPs, hyperplastic polyps, and traditional serrated adenomas, the authors noted.

Although SSPs and traditional serrated adenomas both have significant potential for malignant transformation, SSPs are much more common, making them important targets for research, diagnosis, and possible interventions.

“Previous surveys of cancer-associated mutations in SSP samples, through targeted analysis of limited known mutations, identified the BRAF-V600E as the key mutation in this disease. However, it is not clear whether other mutations in the same samples contribute to the etiology of this disease,” Dr. Jones and his associates wrote.

 

To better understand both the inherited (genetic) and acquired (epigenetic) basis for SSP and tumor development, the investigators used whole-exome sequencing, genome-wide mutation detection, and DNA methylation profiling on multiple samples of both SSPs and FAPs.

They performed exome sequencing on DNA extracted from SSP samples from six patients diagnosed with typical SSP-type colon polyps via colonoscopy and pathology. The samples included one each from five patients and three taken from different portions of the colon in one patient. In all of the samples, BRAF-V600E was the only common somatic mutation detected. In the patient from whom the three SSP samples were taken, the mutation was found in each polyp, but not in grossly uninvolved colon from the same patient.

The investigators next performed genome-wide DNA methylation profiling on 15 colon biopsy samples from 11 patients, including five SSPs, two traditional serrated adenomas, three FAPs, two carcinomas, one grossly uninvolved tissue sample, and two normal tissue samples. They found that the BRAF-V600E mutation correlated with a unique and reproducible DNA methylation signature.

They then determined that the DNA methylation signature that they identified is associated with specific markers for molecular characterization of SSPs, and that these markers showed an approximately 3- to 30-fold increase in methylation levels in only SSP samples.

 

Furthermore, they showed that the unique DNA methylation patterns they identified could be used to distinguish SPPs from adenomatous polyps, with better discrimination than parallel-gene expression profiling.

“The results presented here provide strong evidence that the BRAF-V600E mutation is the main cause of generation of SSP and SSP-specific DNA methylation pattern,” the investigators wrote in the study’s conclusion.

The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. The authors declared no competing financial interests in the work.

 

SOURCE: Dehghanizadeh S et al. PLOS One 13(3): e0192499.

 

Sessile serrated polyps (SSPs), notorious for being difficult to detect and for their potential to become malignant colorectal tumors, appear to be caused by a single oncogenic mutation, a finding that could lead to better early detection of some colorectal cancers through noninvasive stool testing, investigators say.

Using a comprehensive battery of genomic testing and DNA methylation profiling, David Jones, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City and his colleagues compared SSPs with familial adenomatous polyps (FAPs), and found that the V600E mutation in BRAF (V-Raf Murine Sarcoma Viral Oncogene Homolog B) was the sole cancer-causing mutation in SSPs.

They also found a distinct DNA methylation pattern unique to SSPs.

“These SSP-specific methylation patterns effectively distinguish SSP from adenomatous polyps, which could be important for both diagnosis and treatment. It also suggests that the BRAF-V600E mutation directly or indirectly results in the remodeling of the epigenome and that this may set a stage for tumor progression,” they wrote in the open-access journal PLOS One.

Approximately one-third of sporadic colorectal cancers, which account for about 95% of all colorectal malignancies, are thought to arise from premalignant serrated lesions, including SSPs, hyperplastic polyps, and traditional serrated adenomas, the authors noted.

Although SSPs and traditional serrated adenomas both have significant potential for malignant transformation, SSPs are much more common, making them important targets for research, diagnosis, and possible interventions.

“Previous surveys of cancer-associated mutations in SSP samples, through targeted analysis of limited known mutations, identified the BRAF-V600E as the key mutation in this disease. However, it is not clear whether other mutations in the same samples contribute to the etiology of this disease,” Dr. Jones and his associates wrote.

 

To better understand both the inherited (genetic) and acquired (epigenetic) basis for SSP and tumor development, the investigators used whole-exome sequencing, genome-wide mutation detection, and DNA methylation profiling on multiple samples of both SSPs and FAPs.

They performed exome sequencing on DNA extracted from SSP samples from six patients diagnosed with typical SSP-type colon polyps via colonoscopy and pathology. The samples included one each from five patients and three taken from different portions of the colon in one patient. In all of the samples, BRAF-V600E was the only common somatic mutation detected. In the patient from whom the three SSP samples were taken, the mutation was found in each polyp, but not in grossly uninvolved colon from the same patient.

The investigators next performed genome-wide DNA methylation profiling on 15 colon biopsy samples from 11 patients, including five SSPs, two traditional serrated adenomas, three FAPs, two carcinomas, one grossly uninvolved tissue sample, and two normal tissue samples. They found that the BRAF-V600E mutation correlated with a unique and reproducible DNA methylation signature.

They then determined that the DNA methylation signature that they identified is associated with specific markers for molecular characterization of SSPs, and that these markers showed an approximately 3- to 30-fold increase in methylation levels in only SSP samples.

 

Furthermore, they showed that the unique DNA methylation patterns they identified could be used to distinguish SPPs from adenomatous polyps, with better discrimination than parallel-gene expression profiling.

“The results presented here provide strong evidence that the BRAF-V600E mutation is the main cause of generation of SSP and SSP-specific DNA methylation pattern,” the investigators wrote in the study’s conclusion.

The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. The authors declared no competing financial interests in the work.

 

SOURCE: Dehghanizadeh S et al. PLOS One 13(3): e0192499.