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

Author(s)

Vidotto, T. ; Melo, C. M. ; Lautert-Dutra, W. ; Chaves, L. P. ; Reis, R. B. ; Squire, J. A.

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 13, n. 1, p. 13-pg., 2023-03-28.

Abstract

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 9793 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. (AU)

• FAPESP's process: 20/12816-9 - Does ZEB1 cooperate with PTEN loss and TMPRSS2-ERG fusion in prostate cancer immune evasion?
• Grantee: Luiz Paulo Chaves de Souza
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 19/22912-8 - Characterization of the genetic mechanisms leading to immune evasion in the tumor microenvironment of Prostate Cancer
• Grantee: Jeremy Andrew Squire
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/12271-5 - Impact of CDK12 mutation on immune response in prostate cancer
• Grantee: William Lautert Dutra
• Support Opportunities: Scholarships in Brazil - Master