Active BRAF-V600E is the key player in generation of a sessile serrated polyp-specific DNA methylation profile.

Autor: Dehghanizadeh S; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, United States of America., Khoddami V; Department of Cell Biology, Harvard Medical School, Boston, MA, United States of America.; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran., Mosbruger TL; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran., Hammoud SS; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, United States of America.; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States of America., Edes K; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, United States of America., Berry TS; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, United States of America., Done M; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, United States of America., Samowitz WS; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, United States of America., DiSario JA; The Monterey Bay Gastroenterology Research Institute, Monterey, CA, United States of America., Luba DG; The Monterey Bay Gastroenterology Research Institute, Monterey, CA, United States of America., Burt RW; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, United States of America.; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America., Jones DA; Functional and Chemical Genomics, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2018 Mar 28; Vol. 13 (3), pp. e0192499. Date of Electronic Publication: 2018 Mar 28 (Print Publication: 2018).
DOI: 10.1371/journal.pone.0192499
Abstrakt: Background: Sessile serrated polyps (SSPs) have emerged as important precursors for a large number of sporadic colorectal cancers. They are difficult to detect during colonoscopy due to their flat shape and the excessive amounts of secreted mucin that cover the polyps. The underlying genetic and epigenetic basis for the emergence of SSPs is largely unknown with existing genetic studies confined to a limited number of oncogenes and tumor suppressors. A full characterization of the genetic and epigenetic landscape of SSPs would provide insight into their origin and potentially offer new biomarkers useful for detection of SSPs in stool samples.
Methods: We used a combination of genome-wide mutation detection, exome sequencing and DNA methylation profiling (via methyl-array and whole-genome bisulfite sequencing) to analyze multiple samples of sessile serrated polyps and compared these to familial adenomatous polyps.
Results: Our analysis revealed BRAF-V600E as the sole recurring somatic mutation in SSPs with no additional major genetic mutations detected. The occurrence of BRAF-V600E was coincident with a unique DNA methylation pattern revealing a set of DNA methylation markers showing significant (~3 to 30 fold) increase in their methylation levels, exclusively in SSP samples. These methylation patterns effectively distinguished sessile serrated polys from adenomatous polyps and did so more effectively than parallel gene expression profiles.
Conclusions: This study provides an important example of a single oncogenic mutation leading to reproducible global DNA methylation changes. These methylated markers are specific to SSPs and could be of important clinical relevance for the early diagnosis of SSPs using non-invasive approaches such as fecal DNA testing.
Databáze: MEDLINE
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