Active BRAF-V600E is the key player in generation of a sessile serrated polyp-specific DNA methylation profile (WGBS 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. To provide a comprehensive high-resolution SSP-specific DNA methylome from the entire genome, we processed a SSP biopsy sample from one of the patients in our study (#P1-SSP3), confirmed by exome sequencing to harbor BRAFV600E mutation, paired with the grossly uninvolved (GU) colon sample and the blood sample from the same patient, and analyzed them, in parallel, with the whole-genome bisulfite sequencing (WGBS).