Differences in gene expression profiling and biomarkers between histological colorectal carcinoma subsets from the serrated pathway

Abstract

Aims To discern the differences in expression profiling of two histological subtypes of colorectal carcinoma (CRC) arising from the serrated route (serrated adenocarcinoma (SAC) and CRC showing histological and molecular features of a high level of microsatellite instability (hmMSI‐H) both sharing common features (female gender, right‐sided location, mucinous histology, and altered CpG methylation), but dramatically differing in terms of prognosis, development of an immune response, and treatment options. Methods and results Molecular signatures of SAC and hmMSI‐H were obtained by the use of transcriptomic arrays; quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) were used to validate differentially expressed genes. An over‐representation of innate immunity functions (granulomonocytic recruitment, chemokine production, Toll‐like receptor signalling, and antigen processing and presentation) was obtained from this comparison, and intercellular cell adhesion molecule‐1 (ICAM1) was more highly expressed in hmMSI‐H, whereas two genes [those encoding calcitonin gene‐related peptide‐receptor component protein and C‐X‐C motif chemokine ligand 14 (CXCL14)] were more highly expressed in SAC. These array results were subsequently validated by qPCR, and by IHC for CXCL14 and ICAM1. Information retrieved from public databanks confirmed our findings. Conclusions Our findings highlight specific functions and genes that provide a better understanding of the role of the immune response in the serrated pathological route and may be of help in identifying actionable molecules.

The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer

“…In addition, gene expression profiling was carried out in order to clarify the role of the immune response between the two end results of the serrated pathway. As a result, a higher expression of ICAM1 , an adhesion molecule involved in cellular immune responses, and a lower expression of CRCP and CXCL14 were identified in SAC versus hmMSI-H CRCs [132].…”

ColPortal, an integrative multiomic platform for analysing epigenetic interactions in colorectal cancer

“…These methods are expanded versions of descriptions in our related work 11,45 . Total RNA was quantified by spectrometry (NanoDrop ND1000, NanoDrop Technologies, Wilminton, DE) and fragment size distribution was analysed by RNA 6000 Pico Bioanalyzer assay (Agilent Technologies, Palo Alto, CA).…”

Biology and Therapeutic Targets of Colorectal Serrated Adenocarcinoma; Clues for a Histologically Based Treatment against an Aggressive Tumor

“…These genes, along with CXCL14, are upregulated in SAC compared to hmMSI-H, although the cell of origin for this overexpression is elusive, as these genes are normally expressed in myeloid cells, which are not as abundant in SAC as they are in CC or hmMSI-H [27]. ICAM1, however, is more expressed in hmMSI-H than in SAC, which typically favors antigen presentation, is associated with less risk of metastases and is related with a good prognosis due to its association with leukocyte extravasation and improved immune response in the tumor microenvironment [6]. The study of the microtranscriptome has shown a difference in the expression of miR-181-a2, which is lower in SAC than in hmMSI-H.…”

“…Less is known about the serrated pathway, in which a high level of microsatellite instability (MSI-H), high frequency of BRAF mutation and the CpG island methylation phenotype (CIMP) seem to be the leading carcinogenic causes, although significant proportions of SAC are KRAS-mutated and microsatellite-stable [2,3]. These alterations contribute to the development of serrated adenocarcinoma (SAC) and the CRC showing histological and molecular features of MSI-H (hmMSI-H) [4], which are considered as endpoints of this pathway [5,6]. MSI-H is a manifestation of a deficiency in DNA mismatch repair mechanism which has been associated with histological features including the presence of signet-ring cells, mucine, tumor heterogeneity with a medullary component, poor differentiation, "pushing" type tumor growth pattern, peri-and intra-tumoral infiltrating lymphocytes, and "Crohn-like" inflammatory response [7].…”

“…is a significantly lower presence of peritumoral and intratumoral lymphocytic infiltrates [18]. This poorer immune response of SAC is even more dramatic when compared to hmMSI-H, and therefore, transcriptome, micro-transcriptome and methylome studies have supported this histological observation [6,27,28]. These facts, added to the fact that most SACs are microsatellite-stable [2,3], do not make SAC a good candidate for biological therapy targeting the immune-checkpoint.…”