MULTIPLATFORM ANALYSIS OF INTRATUMORAL PTEN HETEROGENEITY IN MELANOMA.
MULTIPLATFORM ANALYSIS OF INTRATUMORAL PTEN HETEROGENEITY IN MELANOMA.
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DOI：
10.1016/j.jid.2023.01.034
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发表时间：
2023-03
期刊：
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通讯作者：
Sharmeen Chagani;M. P. de Macedo;F. Carapeto;Feng Wang;D. Marzese;K. Wani;L. Haydu;W. Peng;Giang T Ong;S. Warren;J. Beechem;D. Hoon;G. Mills;M. Tetzlaff;A. Lazar;L. Kwong;M. Davies
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作者：
Sharmeen Chagani;M. P. de Macedo;F. Carapeto;Feng Wang;D. Marzese;K. Wani;L. Haydu;W. Peng;Giang T Ong;S. Warren;J. Beechem;D. Hoon;G. Mills;M. Tetzlaff;A. Lazar;L. Kwong;M. Davies
肿瘤抑制因子 PTEN 蛋白表达的丧失与黑色素瘤中癌症侵袭性增加、肿瘤免疫浸润减少以及对免疫和靶向治疗的抵抗相关。我们评估了八个具有 PTEN 蛋白表达局部缺失的黑色素瘤样本的独特队列，以了解该疾病中 PTEN 缺失的特征和机制。我们使用 DNA 测序、DNA 甲基化、RNA 表达、数字空间分析和免疫组织化学平台将 PTEN 阴性 (PTEN[−]) 区域与其相邻的 PTEN 阳性 (PTEN[+]) 区域进行比较。在 3 例 (37.5%) 的 PTEN(-) 区域中发现了 PTEN 的变异或纯合性缺失，但在相邻的 PTEN(+) 区域中未检测到，但在其余 PTEN(-) 样本中没有发现明确的基因组或 DNA 甲基化缺失基础。来自两个独立平台的 RNA 表达数据表明，与相邻 PTEN(+) 区域相比，PTEN(-) 区域的染色体分离基因表达持续增加。蛋白质组学分析显示，与邻近的 PTEN(+) 区域相比，PTEN(-) 区域的肿瘤浸润淋巴细胞相对较少。这些发现增强了我们对黑色素瘤中潜在的分子瘤内异质性以及与该疾病中 PTEN 蛋白缺失相关特征的理解。
Loss of protein expression of the tumor suppressorPTENis 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 ofPTENloss 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 ofPTENwere 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.