Gene Signature in Sessile Serrated Polyps Identifies Colon Cancer Subtype

Abstract

Sessile serrated colon adenoma/polyps (SSA/Ps) are found during routine screening colonoscopy and may account for 20–30% of colon cancers. However, differentiating SSA/Ps from hyperplastic polyps (HP) with little risk of cancer is challenging and complementary molecular markers are needed. Additionally, the molecular mechanisms of colon cancer development from SSA/Ps are poorly understood. RNA sequencing was performed on 21 SSA/Ps, 10 HPs, 10 adenomas, 21 uninvolved colon and 20 control colon specimens. Differential expression and leave-one-out cross validation methods were used to define a unique gene signature of SSA/Ps. Our SSA/P gene signature was evaluated in colon cancer RNA-Seq data from The Cancer Genome Atlas (TCGA) to identify a subtype of colon cancers that may develop from SSA/Ps. A total of 1422 differentially expressed genes were found in SSA/Ps relative to controls. Serrated polyposis syndrome (n=12) and sporadic SSA/Ps (n=9) exhibited almost complete (96%) gene overlap. A 51-gene panel in SSA/P showed similar expression in a subset of TCGA colon cancers with high microsatellite instability (MSI-H). A smaller seven-gene panel showed high sensitivity and specificity in identifying BRAF mutant, CpG island methylator phenotype high (CIMP-H) and MLH1 silenced colon cancers. We describe a unique gene signature in SSA/Ps that identifies a subset of colon cancers likely to develop through the serrated pathway. These gene panels may be utilized for improved differentiation of SSA/Ps from HPs and provide insights into novel molecular pathways altered in colon cancer arising from the serrated pathway.

Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing

“…Pathological characterization, tissue preservation, and sample preparation for molecular analyses followed previously reported protocols 40 . Expression data derived from normal left colonic tissue was obtained from a previously published study and was generated from patients undergoing screening colonoscopy with no polyps found on exam 41 (GSE76987).…”

Degree of Tissue Differentiation Dictates Susceptibility to BRAF-Driven Colorectal Cancer

“…Normal tissue from serrated tumor patients is not abundant in the literature, as most studies focus on tumor tissues. Fortunately, a recent study performed transcriptional profiling from mucosal biopsies of non-tumor tissues from the right colons of serrated tumor patients and control individuals (Delker et al, 2014; Kanth et al, 2016). We queried these data to determine whether the differentiation genes that were reduced in pre-neoplastic tissue of our murine models (Figures 2F & 4F) are also reduced in the normal epithelium of patients exhibiting one (sporadic) or multiple (syndromic) serrated tumors.…”

“…Human data comprising RNA-Seq from 25 right colon samples (10 control patients, 10 sporadic SSA tumor patients, and 5 syndromic tumor patients) was derived from non-tumor tissue (Delker et al, 2014; Kanth et al, 2016) (GSE76987). FPKM table was normalized by fold change to the average of the 10 control patient FPKM values for each gene.…”

“…Differentiation signature genes (Chong et al, 2009) and stem cell signature genes (Munoz et al, 2012) that were represented on the the human RNA-Seq FPKM table (GSE76987) (Delker et al, 2014; Kanth et al, 2016), were combined (Table S2), and k-means clustering was performed in R. K-means clustering was performed (clustering of 2) in R, and clustering accuracy was determined using Rand Index (RI) (Rand, 1971), RI=(TP+TN)/(TP+TN+FP+FN). Random gene sets, comprised of an equivalent number of unique genes to our defined gene lists, were selected to establish the ability of random classifiers to stratify patients and applied 1000 times.…”

The Serrated Polyp Pathway: Is It Time to Alter Surveillance Guidelines?

“…However, Schramm et al identified age > 65 (OR, 4.13; 95 % CI 1.22–14.2), snare polypectomy (OR, 23.6; 95 % CI 4.86–115), and concomitant conventional adenomas (OR, 7.56; 95 % CI 1.31–43.5) as predictors of reclassification [56]. Differences in gene expression may also aid pathologists in differentiating between HPs and SSPs [57,58]. However, even low cost interventions such as changes in post-resection handling and simplifying diagnostic criteria have been shown to significantly improve interobserver variation [59].…”