Unsupervised Hierarchical Clustering of Pancreatic Adenocarcinoma Dataset from TCGA Defines a Mucin Expression Profile that Impacts Overall Survival

Abstract

Mucins are commonly associated with pancreatic ductal adenocarcinoma (PDAC) that is a deadly disease because of the lack of early diagnosis and efficient therapies. There are 22 mucin genes encoding large <i>O</i>-glycoproteins divided into two major subgroups: membrane-bound and secreted mucins. We investigated mucin expression and their impact on patient survival in the PDAC dataset from The Cancer Genome Atlas (PAAD-TCGA). We observed a statistically significant increased messenger RNA (mRNA) relative level of most of the membrane-bound mucins (<i>MUC1/3A/4/12/13/16/17/20</i>), secreted mucins (<i>MUC5AC/5B</i>), and atypical mucins (<i>MUC14/18</i>) compared to normal pancreas. We show that <i>MUC1/4/5B/14/17/20/21</i> mRNA levels are associated with poorer survival in the high-expression group compared to the low-expression group. Using unsupervised clustering analysis of mucin gene expression patterns, we identified two major clusters of patients. Cluster #1 harbors a higher expression of <i>MUC15</i> and atypical <i>MUC14</i>/<i>MUC18</i>, whereas cluster #2 is characterized by a global overexpression of membrane-bound mucins (<i>MUC1/4/16/17/20/21</i>). Cluster #2 is associated with shorter overall survival. The patient stratification appears to be independent of usual clinical features (tumor stage, differentiation grade, lymph node invasion) suggesting that the pattern of membrane-bound mucin expression could be a new prognostic marker for PDAC patients.