Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis

Abstract

Serrated colorectal carcinomas (CRCs) are morphologically different from conventional CRCs and have been proposed to follow a distinct pathway of CRC formation. Despite studies of single molecular events in this tumor type, the diagnosis of serrated CRC relies on morphology and the putative unique biological character of these tumors has not been established. Here we show that the gene expression profiling of 37 CRCs separated serrated and conventional CRCs into two distinct branches in unsupervised hierarchical clustering (P-value 7.8 Â 10 À7 ), and revealed 201 differentially expressed genes representing potential biomarkers for serrated CRC. Immunohistochemistry was utilized to verify the key findings in the 37 CRCs examined by expression profiling, and a separate validation set of 37 serrated and 86 conventional CRCs was examined to evaluate the candidate biomarkers in an extended sample material. Ephrin receptor B2, hypoxia-inducible factor 1-alpha and patched appeared as proteins important for genesis of serrated CRC. This study establishes serrated CRCs as a biologically distinct subclass of CRC and represents a step forward in the molecular classification of these cancers. The study also provides a platform to understand the molecular basis of serrated CRC and in long term may contribute to the development of specific treatment options for this tumor type.

Clinicopathological Features of Serrated Adenocarcinoma Defined by Mäkinen in Dukes’ B Colorectal Carcinoma

“…Tuppurainen et al [16 ]reported in 2005 that SAC was not directly related to microsatellite instability and Laiho et al [24] identified in 2007 the ephrin receptor B2, hypoxia-inducible factor 1-alpha and patched (PTCH1) as proteins important for the genesis of SAC. Stefanius et al [25,26 ]did not report any deleterious inactivating PTCH1 mutation in SAC but, in 2011, they observed that SAC is characterized by BRAF and KRAS mutations and it is conceivable that the loss of the PTCH1 protein expression may result from constant activation of the mitogen-activated protein kinase pathway, caused by either KRAS or BRAF mutations.…”

Downregulation of the hedgehog receptor PTCH1 in colorectal serrated adenocarcinomas is not caused by PTCH1 mutations

“…Our earlier RNA expression microarray analysis showed that PTCH1 (patched homolog 1 (Drosophila)) is downregulated and the gene product is lost in serrated carcinomas when compared to conventional CRCs [4]. The PTCH1 gene consists of 23 exons encoding a 1447-amino acid transmembrane glycoprotein with two large ligandbinding extracellular loops and an intracellular N-and Ctermini [5].…”

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

“…9 Sessile serrated adenomas (SSAs) constitute a distinct class of premalignant tumors in the intestine, which are characterized by a saw-toothed and tufted tissue morphology, as well as by unique transcriptional, mutational and epigenetic patterns. [10][11][12] The most prevalent mutation in human SSA is BRAF V600E , representing an oncogenic alteration in the mitogen-activated protein kinase (MAPK) cascade, which is composed of consecutively activated rapidly accelerated fibrosarcoma (RAF), mitogen/extracellular 1 signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK) kinases. In the normal intestine, MAPK activity mainly relays pro-proliferative cues in the progenitor compartment of the upper crypt.…”