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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 13, n. 1, p. 13-pg., 2023-03-28.

Resumo

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)

• Processo FAPESP: 20/12816-9 - O ZEB1 colabora com a perda de PTEN e a fusão TMPRSS2-ERG na evasão tumoral do câncer de próstata?
• Beneficiário: Luiz Paulo Chaves de Souza
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 19/22912-8 - Caracterização dos mecanismos genéticos que levam à evasão imunológica no microambiente tumoral do Câncer de Próstata
• Beneficiário: Jeremy Andrew Squire
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/12271-5 - O impacto da mutação no gene CDK12 na resposta imune do câncer de próstata
• Beneficiário: William Lautert Dutra
• Modalidade de apoio: Bolsas no Brasil - Mestrado