Abstract
The significance of mucins in cancers has led to the development of novel biomarkers and therapeutic agents against cancers. Despite significant advances in the understanding of mucins, systemic investigations into the role of mucins in cancer biology focusing particularly on the histological subtypes and stages, along with other variables, are yet to be carried out to discover potential novel functions and cancer-specific roles. Here, we investigated 11 mucin expressing cancers for DNA mutations, mRNA expression, copy number, methylation, and the impacts these genomic features may have on patient survival by utilizing The Cancer Genome Atlas dataset. We demonstrate that mucin DNA mutations have a significant rate, pattern, and impact on cancer patient survival depending on the tissue of origin. This includes a frequent T112P mutation in MUC1 that is seen in half of the pancreatic MUC1 mutations, as well as being present in other cancers. We also observed a very frequent MUC4 mutation at H4205, which correlated with survival outcomes in patients. Furthermore, we observed significant alterations in mucin mRNA expression in multiple tumor types. Our results demonstrate de novo expression of certain mucins in cancer tissues, including MUC21 in colorectal cancers. We observed a general decrease in promoter methylation for mucins, which correlated with decreased expression of many genes, such as MUC15 in kidney cancers. Lastly, several mucin gene loci demonstrated copy number increase in multiple histological subtypes. Thus, our study presents a comprehensive analysis of genomic alterations in mucins and their corresponding roles in cancer progression.
Highlights
Mucin-based biomarkers have been utilized in clinic for multiple cancers, highlighting the functional significance of mucins in cancer [1, 2]
Considering the significant roles played by mucins in cancer biology and patient survival, it is imperative to investigate the role of the multiple mucins across cancers
The results presented here highlight existing as well as new features, which may serve as potential targets in their respective histological subtypes where cancers are suggested to be utilizing mucin function
Summary
Mucin-based biomarkers have been utilized in clinic for multiple cancers, highlighting the functional significance of mucins in cancer [1, 2]. MUC1, the most studied mucin that is involved in the pathogenesis of the multiple cancer types, serves as a scaffold, a signaling adaptor, a transcriptional co-activator, and a metabolic and immune regulator [7, 8]. It triggers intracellular signaling, leading to transcriptional changes in the nucleus, in response to alterations in the extracellular microenvironment of the tumor cells [8, 9]. MUC13 is another transmembrane mucin that negatively impacts ovarian cancer patient survival, observed to have roles in increasing cancer cell motility and proliferation [10]. Contrary to these cancer-promoting mucins, MUC2 interacts with inflammatory pathways and helps protect against tumor development [10]
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