Two histologically colorectal carcinomas subsets from the serrated pathway show different methylome signatures and diagnostic biomarkers

Abstract

BackgroundAltered methylation patterns are driving forces in colorectal carcinogenesis. The serrated adenocarcinoma (SAC) and sporadic colorectal carcinoma showing histological and molecular features of microsatellite instability (hmMSI-H) are two endpoints of the so-called serrated pathological route sharing some characteristics but displaying a totally different immune response and clinical outcome. However, there are no studies comparing the methylome of these two subtypes of colorectal carcinomas. The methylation status of 450,000 CpG sites using the Infinium Human Methylation 450 BeadChip array was investigated in 48 colorectal specimens, including 39 SACs and 9 matched hmMSI-H.ResultsMicroarray data comparing SAC and hmMSI-H showed an enrichment in functions related to morphogenesis, neurogenesis, cytoskeleton, metabolism, vesicle transport and immune response and also significant differential methylation of 1540 genes, including CD14 and HLA-DOA which were more methylated in hmMSI-H than in SAC and subsequently validated at the CpG, mRNA and protein level using pyrosequencing, quantitative polymerase chain reaction (qPCR) and immunohistochemistry.ConclusionsThese results demonstrate particular epigenetic regulation patterns in SAC which may help to define key molecules responsible for the characteristic weak immune response of SAC and identify potential targets for treating SAC, which lacks molecular targeted therapy.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0571-3) contains supplementary material, which is available to authorized users.

The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer

“…The serrated pathway has two end results that differ in their clinical and prognostic features as well as in their methylome profile: (i) the serrated adenocarcinoma (SAC) or (ii) the sporadic colorectal carcinoma showing histological and molecular features of MSI-H (hmMSI-H) [31,120]. The CRC subtype hmMSI-H is associated with a dense immune infiltrate and shows a better prognosis than SACs [120].…”

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

“…CD14 and HLA-DOA tend to be more methylated in hmMSI-H than in SAC. 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].…”

“…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.…”

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

“…6 Strikingly, these two histological CRC subtypes differ in terms of prognosis, methylome profiling, and treatment options. [7][8][9] SAC has been recognised in the latest World Health Organization classification of tumours of the digestive system as a new subtype of CRC, 10 accounting for 7.5-8.7% of all CRCs. 2,7 SAC has been demonstrated to have a worse prognosis than CC, 7 showing a higher frequency of adverse histological features at the invasive front, including a weak peritumoral lymphocyte response.…”

“…On the basis of common features such as a right‐sided location and the identification of remnants of serrated polyps adjacent to the tumour, it was assumed that serrated adenocarcinoma (SAC) and CRC showing histological and molecular features of MSI‐H (hmMSI‐H) are both endpoints of the serrated pathway . Strikingly, these two histological CRC subtypes differ in terms of prognosis, methylome profiling, and treatment options . SAC has been recognised in the latest World Health Organization classification of tumours of the digestive system as a new subtype of CRC, accounting for 7.5–8.7% of all CRCs .…”