The molecular background of mucinous carcinoma beyond MUC2

Abstract

The increasing interest of the oncology community in tumour classification and prediction of outcome to targeted therapies has put emphasis on an improved identification of tumour types. Colorectal mucinous adenocarcinoma (MC) is a subtype that is characterized by the presence of abundant extracellular mucin that comprises at least 50% of the tumour volume and is found in 10–15% of colorectal cancer patients. MC development is poorly understood, however, the distinct clinical and pathological presentation of MC suggests a deviant development and molecular background. In this review we identify common molecular and genetic alterations in colorectal MC. MC is characterized by a high rate of MUC2 expression. Mutation rates in the therapeutically important RAS/RAF/MAPK and PI3K/AKT pathways are significantly higher in MC compared with non‐mucinous adenocarcinoma. Furthermore, mucinous adenocarcinoma shows higher rates of microsatellite instability and is more frequently of the CpG island methylator phenotype. Although the majority of MCs arise from the large intestine, this subtype also develops in other organs, such as the stomach, pancreas, biliary tract, ovary, breast and lung. We compared findings from colorectal MC with tumour characteristics of MCs from other organs. In these organs, MCs show different mutation rates in the RAS/RAF/MAPK and PI3K/AKT pathways as well, but a common mucinous pathway cannot be identified. Identification of conditions and molecular aberrations that are associated with MC generates insight into the aetiology of this subtype and improves understanding of resistance to therapies.

Associations among histological characteristics and patient outcomes in colorectal carcinoma with a mucinous component

“…Mucinous CRC have higher rates of MSI 25 and lower rates of TP53 mutation than adenocarcinoma, 26 and they also demonstrate higher expression of HATH1 27 and MUC2. 28 KRAS mutation may 29 or may not 26 be related to mucinous differentiation in CRC. Some of these associations are important from a prognostic and therapeutic perspective, as MSI-high status confers improved survival in mCRC 25 and may qualify a patient for anti-PD-1 therapy, 30 and tumours with a KRAS mutation are not eligible for treatment with EGFR inhibitors.…”

Mucinous adenocarcinoma of the colon and rectum: A genomic analysis

“…MUC5B, MUC6, MUC14, MUC16, and MUC18 were the genes that were implicated although one cannot be sure if the increased rate of SSMs in these genes accounts for the end result which is the production of mucin and resistance to chemoradiotherapy in this histological subtype, further studies looking at gene expression data may prove to be more useful to determine the molecular alterations behind mucinous histology. 32 Mucinous tumors had more alteration in the cell cycle, the RTK-RAS, and the TGF-β pathways compared with non-mucinous tumors which had more alterations in the TP53 pathway. Interestingly, more CNA gain was found in the ARRDC and the RICTOR genes in the mucinous cohort, both of these genes play a role in cancer growth and progression as well as cell Stratifying patients in this way may be important when determining treatment and prognosis.…”

Impact of Global DNA Methylation in Treatment Outcome of Colorectal Cancer Patients

“…Cancer cells have many aberrant transcripts of DNMT3B, which is linked to E -cadherin promoter gene methylation and CRC aggressiveness ( Brambert et al, 2015 ). Moreover, DNMT3B overexpression was frequently associated with LINE-1 hypermethylation, high-grade histology with many features of combined high MSI, CIMP and BRAF V600E mutation and increased KRAS and wild-type p53 expressions ( Hugen et al, 2015 ).…”

“…DNMT3B causes hypermethylation of promoter CpG-rich regions in a variety of malignancies ( Yun et al, 2012 ) and repress transcription in either methylation-dependent manner ( Linhart et al, 2007 ; Nosho et al, 2009 ) or through their histone deacetylase activity ( Fuks et al, 2001 ). Moreover, DNMT3B overexpression was frequently associated with LINE-1 hypermethylation, high-grade histology with many features of combined high MSI, CIMP and BRAF V600E mutation and increased KRAS and wild-type p53 expressions ( Hugen et al, 2015 ).…”