Pan-cancer genomic analysis shows hemizygousPTENloss tumors are associated with immune evasion and poor outcome

Abstract

ABSTRACTIn tumors, somatic mutations of thePTENsuppressor gene are associated with advanced disease, chemotherapy resistance, and poor survival.PTENloss of function may occur by inactivating mutation, by deletion, either affecting one copy (hemizygous loss) leading to reduced gene expression or loss of both copies (homozygous) with expression absent. Various murine models have shown that minor reductions in PTEN protein levels strongly influence tumorigenesis. MostPTENbiomarker assays dichotomize PTEN (i.e. presence vs. absence) ignoring the role of one copy loss. We performed aPTENcopy number analysis of 9,793 TCGA cases from 30 different tumor types. There were 419 (4.28%) homozygous and 2484 (25.37%) hemizygousPTENlosses. Hemizygous deletions led to reduced PTEN gene expression, accompanied by increased levels of instability and aneuploidy across tumor genomes. Outcome analysis of the pan-cancer cohort showed that losing one copy ofPTENreduced survival to comparable levels as complete loss, and was associated with transcriptomic changes controlling immune response and the tumor microenvironment. Immune cell abundances were significantly altered forPTENloss, with changes in head and neck, cervix, stomach, prostate, brain, and colon more evident in hemizygous loss tumors. These data suggest that reduced expression ofPTENin tumors with hemizygous loss leads to tumor progression and influences anticancer immune response pathways.