Recent advances in colorectal cancer (CRC) research have demonstrated that CRC is a heterogeneous entity and challenges the paradigm that all colorectal carcinomas arise exclusively via the traditional adenoma-carcinoma sequence1. The emergence of sessile serrated adenoma (SSA) as a precursor lesion of CRC, and its morphological similarity to common hyperplastic polyps (HP), presents a major challenge for the early detection and management of CRC and its precursors. While the exact percentage of CRC arising through the serrated pathway is unknown it is estimated to be as high as 20-30% of all CRC2. However, objective morphological factors and biomarkers of the serrated pathway remain to be defined. Here we describe gene expression profiling studies (Affymetrix gene arrays) between morphologically distinct CRC precursor lesions characterised by BRAF mutation status, i.e. BRAFV600E mutation positive (n=5) vs. negative lesions (n=5). Pathway analysis of differentially expressed genes (Ingenuity Pathway Analysis) revealed dysregulated cell surface-mediated signalling and altered cellular metabolism and immune response as being potentially involved in the development of SSA. qRT-PCR was used to investigate claudin-1 expression changes in SSA (n=18) and HP (n=11) samples. Claudin-1 expression was significantly up-regulated in SSA when compared to HP (p<0.0003). Immunohistochemical analysis was performed to further validate these findings. Claudin-1 expression was compared between SSA with BRAF V600E mutation (n=53), HP with BRAF V600E mutation (n=111), HP with mutations in KRAS (n=23), and HP without mutation in either the BRAF or KRAS genes (n=35). Elevated claudin-1 expression strongly correlated with BRAF V600E mutation status in both SSA and HP samples when compared to HP with KRAS mutation (p<0.0001) or HP no mutation in either gene (p<0.0001). Based on gene expression analysis, we provide evidence that serrated polyps are a novel subtype of colorectal precursor lesions and identify claudin-1 as a potential biomarker of the serrated pathway.