Lautert-Dutra, W. | Search bioRxiv

bioRxiv2022

Pan-genomic analysis shows hemizygous PTEN loss tumors are associated with immune evasion and poor outcome

In tumors, somatic mutations of the PTEN suppressor gene are associated with advanced disease, chemotherapy resistance, and poor survival. PTEN loss 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. Most PTEN biomarker assays dichotomize PTEN (i.e. presence vs. absence) ignoring the role of one copy loss. We performed a PTEN copy number analysis of 9,793 TCGA cases from 30 different tumor types. There were 419 (4.28%) homozygous and 2484 (25.37%) hemizygous PTEN losses. 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 of PTEN reduced 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 for PTEN loss, with changes in head and neck, cervix, stomach, prostate, brain, and colon more evident in hemizygous loss tumors. These data suggest that reduced expression of PTEN in tumors with hemizygous loss leads to tumor progression and influences anticancer immune response pathways.

cancer biology↗

bioRxiv2022

Quantitative MHC class-I/-II expression levels in CDK12 mutated prostate cancer patients reveal intratumorally T cell adaptive immune response in tumors

BackgroundCDK12 inactivation is a predictive biomarker for immune checkpoint blockers (ICB) treatment response in advanced prostate cancer (PCa), but some CDK12-altered patients fail to respond to ICB. Downregulation of MHC expression has been described as a mechanism of intrinsic and acquired resistance to ICB in various cancers, but there is little information on whether MHC expression levels are altered in CDK12 defective PCa that fails to respond to ICB treatments. MethodsUsing genomics data of primary and metastatic prostate cancer from two public domain cohorts and a retrospective cohort, we investigated variation in the expression of the MHC genes and associated downstream changes in CDK12 mutated patients. The findings of public domain data were validated using transcriptomic data from a 53-patient retrospective cohort from our Institute. ResultsBased on the analysis of gene expression quartiles, we divided the tumors into "High" and "Low" expression levels of MHC-I and -II. CDK12 defective tumors with increased MHC levels showed the activation of several pathways associated with the immune system and elevated PD-L1, IDO1, and TIM3 expression. These transcriptomic findings were confirmed using expression analyses of our cohort of 53 primary PCa. There was an increased composition of CD8+ T cells, B cells, {gamma}{delta} T cells, and M1 Macrophages in CDK12 mutated tumors with elevated MHC levels based on digital cytometric analyses. In contrast, CDK12 defective tumors with decreased MHC expression were often subject to loss of heterozygosity (LOH) genomic events affecting MHC-I/-II and the HLA gene cluster on chromosome 6. CDK12 defective PCa expresses higher levels of classical MHC, has an active and inflamed tumor microenvironment, and increases the presence of effector T cells. ConclusionsReduced MHC expression may be caused by the acquisition of specific somatic genomic events that reduce the expression of antigen presentation genes. Combining CDK12 mutation, MHC expression levels, and LOH status may better predict outcomes for ICB-eligible PCa. In addition, these findings draw attention to the need to investigate therapeutic approaches for enhancing MHC expression in CDK12 defective PCa to improve ICB responses.

cancer biology↗