Chromosomally and microsatellite stable colorectal carcinomas without the CpG island methylator phenotype in a molecular classification

Abstract

Abstract. We hypothesized that in a comprehensive analysis of colorectal carcinomas (CRC) the three currently known major molecular mechanisms of carcinogenesis (i.e., chromosomal instability, microsatellite instability, and CpG island methylator phenotype, CIMP) would associate with the molecular features indicative of these pathways, allowing a molecular classification. A prospectively collected clinicopathologically well-characterized series of 130 CRCs was tested for chromosomal instability (DNA-flow cytometry and analysis of allelic imbalance with microsatellite markers 5q21, 8p21, 9q21, 17p13, and 18q21), microsatellite instability (Bethesda panel), CIMP (MethyLight), and mutations of K-ras, B-raf, APC, and p53. Morphology was reviewed, and nuclear ß-catenin translocation was assessed by immunohistochemistry. Based on the molecular features, sporadic high-degree microsatellite instable tumours, tumours of the hereditary non-polyposis coli carcinoma syndrome, and 'sporadic standard-type' CRC could be delineated (14, 4, and 55, respectively). However, overlap between classes was seen for 46 of the remaining tumours where widespread or occasional methylations (excluding MLH1) were observed, and the majority had chromosomal instability. Importantly, a group of 11 tumours was observed without either microsatellite or chromosomal instability, nor any methylation. Morphologically, these tumours were without any distinguishing features, all had tumour budding and 10 showed nuclear ß-catenin translocation. Overall, the data give an overview of the molecular classes in CRC that should be taken into account in studies on carcinogenesis and clinicopathological studies. Specifically, the absence of CIN, MSI, and CIMP in an 8.46% fraction of tumours delineates a group to be aware of.

Tumor Take Rate Optimization for Colorectal Carcinoma Patient-Derived Xenograft Models

“…A basic analysis of relevant mutations for CRC and further genetic features performed side by side with the PDX models and the primary tumors also revealed no differences (Table 3(b)). Accordingly, HROC107 could be classified as a sporadic standard type CRC whereas HROC131 is sporadic microsatellite instable (Table 3(b); classification according to [3]) CRC.…”

“…Subsequently, major developments were accomplished in defining the main molecular classes of CRC as chromosomal and microsatellite instability and the CpG island methylator phenotype, which are recognized as key pathogenetic mechanisms [2, 3]. The analysis of these fundamental sequences led to five molecular subtypes of CRC [3, 4].…”

“…Subsequently, major developments were accomplished in defining the main molecular classes of CRC as chromosomal and microsatellite instability and the CpG island methylator phenotype, which are recognized as key pathogenetic mechanisms [2, 3]. The analysis of these fundamental sequences led to five molecular subtypes of CRC [3, 4]. As a result of these discoveries, additional mutational analyses have revealed that in an individual cancer only a limited number of pathways are dysregulated by some “driver” mutations from a circumscribed number of about 80 candidate cancer genes [5, 6].…”

Endogenous retrovirus sequences as a novel class of tumor-specific antigens: an example of HERV-H env encoding strong CTL epitopes

“…This would thus be especially interesting for microsatellite-instable and CpG-island methylation-high CRCs, both with typically low levels of chromosomal instability [24]. Respective analyses are currently being performed in our laboratory using a panel of primary CRC cell lines of the diVerent molecular classes.…”

The HROC-Xenobank—A High Quality Assured PDX Biobank of >100 Individual Colorectal Cancer Models

“…Since an ideal CRC PDX collection should approximate the molecular heterogeneity of clinical cases, our 125 PDX were classified according to the following molecular subtypes [17]: chromosomal instable (CIN), sporadic microsatellite instable (spMSI), having the CpG island methylator phenotype (CIMP, sub classified into high level (CIMP-H) and low-level (CIMP-L)), and Lynch syndrome (LS) (Table 2). The distribution of the molecular subtypes mostly corresponds to the general clinical distribution [28].…”