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Germline variants of  PIP4K2A  impact susceptibility of acute lymphoblastic leukemia (ALL) through inducing its overexpression. Although limited reports suggested the oncogenic role of  PIP4K2A  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  PIP4K2A  and its related genes in multiple cancer types. 214 candidates were identified to be significantly associated with  PIP4K2A  expression in ALL patients, with known cancer-related genes rankings the top (e.g.,  RAC2 ,  RBL2 , and  TFDP1 ). 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.  PIP4K2A  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,  PIP4K2A  and its related candidates exhibit stage-independent prognostic effects in multiple cancers, mostly with its lower expression significantly associated with longer overall survival ( p  < 0.05). Our findings reveal the transcriptional regulatory network of  PIP4K2A  in leukemia, and suggest its potentially important role on molecular subtypes of multiple cancers and subsequent treatment outcomes.

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