Regulatory Network and Prognostic Effect Investigation of PIP4K2A in Leukemia and Solid Cancers

Abstract

Germline variants of <i>PIP4K2A</i> impact susceptibility of acute lymphoblastic leukemia (ALL) through inducing its overexpression. Although limited reports suggested the oncogenic role of <i>PIP4K2A</i> in cancers, regulatory network and prognostic effect of this gene remains poorly understood in tumorigenesis and leukemogenesis. In this study, we conducted genome-wide gene expression association analyses in pediatric B-ALL cohorts to discover expression associated genes and pathways, which is followed by the bioinformatics analyses to investigate the prognostic role of <i>PIP4K2A</i> and its related genes in multiple cancer types. 214 candidates were identified to be significantly associated with <i>PIP4K2A</i> expression in ALL patients, with known cancer-related genes rankings the top (e.g., <i>RAC2</i>, <i>RBL2</i>, and <i>TFDP1</i>). These candidates do not only tend to be clustered in the same types of leukemia, but can also separate the patients into novel molecular subtypes. <i>PIP4K2A</i> is noticed to be frequently overexpressed in multiple other types of leukemia and solid cancers from cancer cohorts including TCGA, and associated with its candidates in subtype-specific and cancer-specific manners. Interestingly, the association status varied in tumors compared to their matched normal tissues. Moreover, <i>PIP4K2A</i> and its related candidates exhibit stage-independent prognostic effects in multiple cancers, mostly with its lower expression significantly associated with longer overall survival (<i>p</i> < 0.05). Our findings reveal the transcriptional regulatory network of <i>PIP4K2A</i> in leukemia, and suggest its potentially important role on molecular subtypes of multiple cancers and subsequent treatment outcomes.