PTEN公司
癌症研究
生物
抑癌基因
黑色素瘤
癌症
PI3K/AKT/mTOR通路
癌变
遗传学
信号转导
作者
Sharmeen Chagani,Mariana Petaccia de Macedo,Fernando Carapeto,Feng Wang,Diego M. Marzese,Khalida Wani,Lauren E. Haydu,Weiyi Peng,Giang T. Ong,Sarah Warren,Joseph M. Beechem,Dave S. B. Hoon,Gordon B. Mills,Michael T. Tetzlaff,Alexander J. Lazar,Lawrence N. Kwong,Michael A. Davies
标识
DOI:10.1016/j.jid.2023.01.034
摘要
Loss of protein expression of the tumor suppressor PTEN is associated with increased cancer aggressiveness, decreased tumor immune infiltration, and resistance to immune and targeted therapies in melanoma. We assessed a unique cohort of eight melanoma samples with focal loss of PTEN protein expression to understand the features and mechanisms of PTEN loss in this disease. We compared the PTEN-negative (PTEN[−]) areas to their adjacent PTEN-positive (PTEN[+]) areas using DNA sequencing, DNA methylation, RNA expression, digital spatial profiling, and immunohistochemical platforms. Variations or homozygous deletions of PTEN were identified in PTEN(−) areas that were not detected in the adjacent PTEN(+) areas in three cases (37.5%), but no clear genomic or DNA methylation basis for loss was identified in the remaining PTEN(−) samples. RNA expression data from two independent platforms identified a consistent increase in chromosome segregation gene expression in PTEN(−) versus adjacent PTEN(+) areas. Proteomic analysis showed a relative paucity of tumor-infiltrating lymphocytes in PTEN(−) versus adjacent PTEN(+) areas. The findings add to our understanding of potential molecular intratumoral heterogeneity in melanoma and the features associated with the loss of PTEN protein in this disease. Loss of protein expression of the tumor suppressor PTEN is associated with increased cancer aggressiveness, decreased tumor immune infiltration, and resistance to immune and targeted therapies in melanoma. We assessed a unique cohort of eight melanoma samples with focal loss of PTEN protein expression to understand the features and mechanisms of PTEN loss in this disease. We compared the PTEN-negative (PTEN[−]) areas to their adjacent PTEN-positive (PTEN[+]) areas using DNA sequencing, DNA methylation, RNA expression, digital spatial profiling, and immunohistochemical platforms. Variations or homozygous deletions of PTEN were identified in PTEN(−) areas that were not detected in the adjacent PTEN(+) areas in three cases (37.5%), but no clear genomic or DNA methylation basis for loss was identified in the remaining PTEN(−) samples. RNA expression data from two independent platforms identified a consistent increase in chromosome segregation gene expression in PTEN(−) versus adjacent PTEN(+) areas. Proteomic analysis showed a relative paucity of tumor-infiltrating lymphocytes in PTEN(−) versus adjacent PTEN(+) areas. The findings add to our understanding of potential molecular intratumoral heterogeneity in melanoma and the features associated with the loss of PTEN protein in this disease.
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