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

“…Although properly identifying that the mucinous subtype of CRC may not have prognostic significance, it may connote potentially important biological and therapeutic information. Mucinous CRC have higher rates of MSI and lower rates of TP53 mutation than adenocarcinoma, and they also demonstrate higher expression of HATH1 and MUC2 . KRAS mutation may or may not be related to mucinous differentiation in CRC.…”

Prognostic Implications of Mucinous Differentiation in Metastatic Colorectal Carcinoma Can Be Explained by Distinct Molecular and Clinicopathologic Characteristics

“…Since these mutations are characteristic of the mucinous subtype, our results may be indicating a potential function of mutant GNAS in the pathogenesis of mucinous CRC. Similarly, SMAD4 and ERBB2 mutations may also be associated with mucinous histology [9,39], however, their contribution to its clinical correlates is vaguely understood.…”

Mucinous Adenocarcinomas Histotype Can Also be a High-Risk Factor for Stage II Colorectal Cancer Patients

“…Above all, research on molecular variations might help to identify MA patients with a higher risk for malignant tumor behavior in terms of survival. For example, in comparison with AD, MA has microsatellite instability more frequently, indicating an alternative oncogenic pathway contributing to the disease [19]. Whenever microsatellite stability was observed, however, a notably reduced rate of copy-number aberrations was characterized in MA when compared to that in AD [20].…”

“…Whenever microsatellite stability was observed, however, a notably reduced rate of copy-number aberrations was characterized in MA when compared to that in AD [20]. In addition, active BRAF mutations were more frequently found in patients with MA and were associated with an infiltrative pattern of tumor growth [18,19]. In the end, loss of the p53 gene, which plays a vital role in regulating the cell cycle, led to uncontrolled tissue growth and aggressive tumors.…”