1. SSA/Ps Syndromic SSA/Ps Sporadic HPs Sporadic 63284600 9 342 236 124 Genes differentially expressed ≥ 2-fold in syndromic and sporadic SSA/Ps and hyperplastic polyps by RNA sequencing. Differentially expressed genes with ≥ 2- fold change and FDR < 0.05 in syndromic SSA/Ps (n=12), sporadic SSA/Ps (n=9) and HPs (n=10) compared to control colon. Syndromic and sporadic SSA/Ps were compared to control right colon (n=10) and HPs were compared to control left colon (n=10). 1350, 698 and 711 genes were differentially expressed in syndromic and sporadic SSA/Ps and HPs, respectively. 1422 genes total were differentially expressed in syndromic and/or sporadic SSA/Ps. Supplemental Figure 1

2. Supplemental Figure 2 Log 2 Ratio Color Bar SporadicRight_2 SyndromicRight_5 SyndromicRight_1 SyndromicRight_2 SporadicRight_1 SporadicLeft_2 SyndromicRight_3 SyndromicRight_4 ControlRight_6 SporadicLeft_1 SyndromicLeft_1 ControlRight_10 ControlRight_4 ControlRight_9 ControlRight_8 ControlRight_1 ControlRight_3 ControlRight_5 ControlRight_7 ControlRight_2 Comparison of gene expression in uninvolved colon from patients with SSA/Ps with control colon from patients without polyps. Relative expression of 1922 genes found differentially expressed (Fold ≥ 2 and FDR < 0.01) between uninvolved (n=10, 7 right and 3 left) and control right colon (n=10). Uninvolved colon includes six uninvolved colon from syndromic patients with SSA/Ps and four uninvolved colon from sporadic patients with SSA/Ps. Log 2 ratios comparing each individual sample to the mean of 10 right control colon samples was used for hierarchical clustering.

3. Supplemental Figure 3 Log 2 Ratio Color Bar Evaluation of an SSA/P gene signature using previously published microarray data of SSA/Ps, MVHPs and control colon. Quantile normalized expression data for each signature gene was downloaded from the Gene Expression Omnibus (GEO) under accession number GSE43841. Expression data from six SSA/Ps, six MVHPs and six control colon FFPE samples (three right and three left) was evaluated for expression of our gene markers. Hierarchical clustering of log 2 ratio values comparing each individual colon sample (SSA/P – sessile serrated adenoma/polyp, MVHP – microvesicular hyperplastic polyp, CTRL – control colon) to the mean of all 18 colon samples is shown. Red and green denote overexpression and underexpression, respectively. Clustering was performed using a correlation metric and complete linkage.

4. Supplemental Figure 4 mRNA expression of four SSA/P signature genes (FSCN1, MUC6, SEMG1 and ZIC5) in SSA/Ps, HPs, uninvolved colon and control colon by quantitative RT-PCR (qPCR). mRNA expression for each gene was determined using commercially available TaqMan gene expression assays (Invitrogen) and a Applied Biosystems 7900HT real-time PCR instrument. 10ul qPCR reactions were performed with forward and reverse primers, internal probe, master mix and 10-15 ng cDNA. cDNA was made from total RNA using the High Capacity RNA to cDNA kit (Invitrogen). A total of 73 samples were analyzed, 21 SSA/Ps, 12 HPs, 17 uninvolved and 23 control colon. Beta-actin was used a reference and control colon as the baseline for determining fold change using the ΔΔCT method. Statistical significance was determined by the non-parametric Mann Whitney U test.