Distinct subtypes of genomic PTEN deletion size influence the landscape of aneuploidy and outcome in prostate cancer

Autor(es)

Vidotto, Thiago ^[1] ; Tiezzi, Daniel Guimaraes ^[2] ; Squire, Jeremy A. ^{[3, 1, 4]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ribeirao Preto - Brazil

^[2] Clin Hosp Ribeirao Preto, Dept Gynecol & Obstet, Ribeirao Preto - Brazil

^[3] Queens Univ, Dept Pathol & Mol Med, Kingston, ON - Canada

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol & Legal Med, 3900 Bandeirantes Ave, BR-14040900 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR CYTOGENETICS; v. 11, JAN 3 2018.
• Citações Web of Science: 7

Resumo

Background: Inactivation of the PTEN tumor suppressor gene by deletion occurs in 20-30% of prostate cancer tumors and loss strongly correlates with a worse outcome. PTEN loss of function not only leads to activation of the PI3K/AKT pathway, but is also thought to affect genome stability and increase levels of tumor aneuploidy. We performed an in silico integrative genomic and transcriptomic analysis of 491 TCGA prostate cancer tumors. These data were used to map the genomic sizes of PTEN gene deletions and to characterize levels of instability and patterns of aneuploidy acquisition. Results: PTEN homozygous deletions had a significant increase in aneuploidy compared to PTEN tumors without an apparent deletion, and hemizygous deletions showed an intermediate aneuploidy profile. A supervised clustering of somatic copy number alterations (SCNA) demonstrated that the size of PTEN deletions was not random, but comprised five distinct subtypes: (1){''}Small Interstitial{''} (70 bp-789Kb); (2) ``Large Interstitial{''} (1-7 MB); (3) ``Large Proximal{''} (3-65 MB); (4) ``Large Terminal{''} (8-64 MB), and (5) ``Extensive{''} (71-132 MB). Many of the deleted fragments in each subtype were flanked by low copy repetitive (LCR) sequences. SCNAs such as gain at 3q21.1-3q29 and deletions at 8p, RB1, TP53 and TMPRSS2-ERG were variably present in all subtypes. Other SCNAs appeared to be recurrent in some deletion subtypes, but absent from others. To determine how the aneuploidy influenced global levels of gene expression, we performed a comparative transcriptome analysis. One deletion subtype (Large Interstitial) was characterized by gene expression changes associated with angiogenesis and cell adhesion, structure, and metabolism. Logistic regression demonstrated that this deletion subtype was associated with a high Gleason score (HR = 2.386; 95% C. I. 1.245-4.572), extraprostatic extension (HR = 2.423, 95% C. I. 1.157-5.075), and metastasis (HR = 7.135; 95% C. I. 1.540-33.044). Univariate and multivariate Cox Regression showed that presence of this deletion subtype was also strongly predictive of disease recurrence. Conclusions: Our findings indicate that genomic deletions of PTEN fall into five different size distributions, with breakpoints that often occur close LCR regions, and that each subtype is associated with a characteristic aneuploidy signature. The Large Interstitial deletion had a distinct gene expression signature that was related to cancer progression and was also predictive of a worse prognosis. Keywords: TCGA, Prostate cancer, Genomic (AU)

• Processo FAPESP: 15/09111-5 - Investigação de Biomarcadores Genômicos para Aplicação Clínica no Câncer de Próstata
• Beneficiário: Jeremy Andrew Squire
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/22785-5 - O Papel da Perda do Gene PTEN na Facilitação da Resposta Inflamatória no Câncer de Prótata
• Beneficiário: Thiago Vidotto
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/02730-4 - Propriedades de reversão tumorigênica usando 5-aza-DC e TSA na metilação do DNA e na progressão do câncer de mama
• Beneficiário: Fernanda Marques Rey
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado