GSE110535
Active BRAF-V600E is the key player in generation of a sessile serrated polyp-specific DNA methylation profile (Exome-seq data set)
Screening and surveillance of colorectal cancers (CRCs) using advanced colonoscopy technologies have significantly reduced the incidence and mortality rates of CRCs in recent years. However, a significant portion of CRCs are still remained undiagnosed, especially those involving sessile serrated adenomas/polyps (SSA/P), most likely due to their flat shape and the excessive amounts of secreted mucin that cover the polyps, making them invisible for colonoscopy. Here, a potential alternative solution is the application of molecular markers enabling unambiguous characterization of SSPs. However, full implementation of this strategy requires availability of robust markers which are still lacking. In this work by comprehensive molecular analysis of several malignant and normal samples at the genome, methylome and transcriptome levels we show that activating mutation of BRAF-V600E drives the generation of a unique SSP-specific DNA methylation profile. As the result a robust set of DNA methylation markers showing significant (~3 to 30 fold) increase in their methylation levels, exclusively in SSP samples, are introduced. These markers can be of important clinical relevance, especially in early diagnosis of SSPs using non-invasive approaches such as fecal DNA testing. Overall design: To verify previous “targeted” mutational analysis reports claiming that BRAFV600E is the main mutation in common between different sessile serrated polyp (SSP) samples, we performed a comprehensive exome sequencing on DNA extracted from total of eight SSP samples from six patients diagnosed, via colonoscopy and pathological inspection of polyp sections, to have typical SSP type polyps in their colons. From five of these patients a single polyp was analyzed to study the common mutations between different affected individuals. From the sixth patient three different polyps were isolated from different locations of the colon, providing the opportunity to separately sequence the DNA extracted from all three samples to study the possible differences between different polyps of the same individual. In parallel to these eight SSP samples, exome sequencing was performed on corresponding available paired blood samples (from four patients; including the one with three different polyps) to filter the germline mutations and single nucleotide polymorphisms (SNPs).