Integrating thousands of PTEN variant activity and abundance measurements reveals variant subgroups and new dominant negatives in cancers.
Integrating thousands of PTEN variant activity and abundance measurements reveals variant subgroups and new dominant negatives in cancers.
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DOI：
10.1186/s13073-021-00984-x
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发表时间：
2021-10-14
期刊：
影响因子：
12.3
通讯作者：
Fowler DM
中科院分区：
文献类型：
--
作者：
Matreyek KA;Stephany JJ;Ahler E;Fowler DM
PTEN是一种多功能的肿瘤抑制蛋白，调节细胞生长、免疫信号、神经功能和基因组稳定性。实验特征有助于指导临床对在患者中观察到的数千种生殖系或体细胞PTEN变体的解释。最近公布了两个大规模突变数据集，一个是PTEN变异细胞内丰度的数据集，包含4112个错义变异体，另一个是脂磷酸酶活性的数据集，包含7244个变异体。来自这些数据集的综合信息可以揭示可能支撑各种临床表现的变异特有的表型，但这还没有得到全面的检查，特别是在癌症中观察到的体细胞PTEN变异。在这里，我们通过测量764个新的PTEN变种的细胞内丰度和改进3351个以前研究的变种的丰度测量来增加这些努力。我们使用这个扩展和改进的PTEN丰度数据集来探索控制PTEN细胞内丰度的突变模式，然后结合磷酸酶活性数据将PTEN变体细分为四个功能不同的组。这一分析揭示了一组高度丰富但有脂质磷酸酶缺陷的变异体，它们可以以显性-负向的方式抑制PTEN活性。其中两个变异体确实能够在携带WT PTEN等位基因的细胞中失调Akt信号。在多发性乳腺或子宫肿瘤中观察到了这两种变异，证明了这些高丰度、不活跃的变异与疾病相关。我们表明，多维的、大规模的变异功能数据，当与公共癌症基因组数据集和后续分析相结合时，可以提高对未表征的癌症相关变异的理解，并提供对它们如何促进肿瘤发生的更好的洞察。网上版载有补充材料，可在10.1186/s13073-021-00984-x查阅。
PTEN is a multi-functional tumor suppressor protein regulating cell growth, immune signaling, neuronal function, and genome stability. Experimental characterization can help guide the clinical interpretation of the thousands of germline or somatic PTEN variants observed in patients. Two large-scale mutational datasets, one for PTEN variant intracellular abundance encompassing 4112 missense variants and one for lipid phosphatase activity encompassing 7244 variants, were recently published. The combined information from these datasets can reveal variant-specific phenotypes that may underlie various clinical presentations, but this has not been comprehensively examined, particularly for somatic PTEN variants observed in cancers. Here, we add to these efforts by measuring the intracellular abundance of 764 new PTEN variants and refining abundance measurements for 3351 previously studied variants. We use this expanded and refined PTEN abundance dataset to explore the mutational patterns governing PTEN intracellular abundance, and then incorporate the phosphatase activity data to subdivide PTEN variants into four functionally distinct groups. This analysis revealed a set of highly abundant but lipid phosphatase defective variants that could act in a dominant-negative fashion to suppress PTEN activity. Two of these variants were, indeed, capable of dysregulating Akt signaling in cells harboring a WT PTEN allele. Both variants were observed in multiple breast or uterine tumors, demonstrating the disease relevance of these high abundance, inactive variants. We show that multidimensional, large-scale variant functional data, when paired with public cancer genomics datasets and follow-up assays, can improve understanding of uncharacterized cancer-associated variants, and provide better insights into how they contribute to oncogenesis. The online version contains supplementary material available at 10.1186/s13073-021-00984-x.
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