扩大癌症中 BAP1 改变的检测范围和影响。

IF 3.2 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
NAR cancer Pub Date : 2024-11-15 eCollection Date: 2024-12-01 DOI:10.1093/narcan/zcae045
Ian R Sturgill, Jesse R Raab, Katherine A Hoadley
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引用次数: 0

摘要

BAP1(BRCA 相关蛋白 1)肿瘤抑制基因的异常表达是几种肿瘤类型的一个重要风险因素,在肿瘤的演变和发展中起着重要作用。在这里,我们利用《癌症基因组图谱》(The Cancer Genome Atlas)中 33 种癌症类型和 10,000 多人的数据进行了综合多组学分析,以确定导致 BAP1 干扰的变异。我们将现有的变异调用和来自多个独立变异调用者的从头局部重配管道的新调用结合起来,将体细胞变异的检测率提高了 41%,从 182 个增加到 257 个,其中包括 11 个≥40 bp 的嵌合体。突变检测范围的扩大凸显了新工具在发现较长嵌合和有影响突变方面的能力。我们开发了一种基于表达的 BAP1 活性评分,并确定了癌症中与 BAP1 干扰相关的转录谱。BAP1被认为在控制肿瘤可塑性和正常细胞命运方面起着关键作用。利用人类和小鼠肝脏数据集,正常细胞中 BAP1 的缺失会导致 BAP1 活性评分降低,而评分降低则与胚胎细胞的低分化表型有关。总之,我们扩大的 BAP1 突变体样本揭示了癌细胞中的转录特征,支持了 BAP1 对细胞可塑性和细胞特性维持的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Expanded detection and impact of BAP1 alterations in cancer.

Aberrant expression of the BAP1 (BRCA associated protein 1) tumor suppressor gene is a prominent risk factor for several tumor types and is important in tumor evolution and progression. Here we performed integrated multi-omics analyses using data from The Cancer Genome Atlas for 33 cancer types and over 10 000 individuals to identify alterations leading to BAP1 disruption. We combined existing variant calls and new calls derived from a de novo local realignment pipeline across multiple independent variant callers, increasing somatic variant detection by 41% from 182 to 257, including 11 indels ≥40 bp. The expanded detection of mutations highlights the power of new tools to uncover longer indels and impactful mutations. We developed an expression-based BAP1 activity score and identified a transcriptional profile associated with BAP1 disruption in cancer. BAP1 has been proposed to play a critical role in controlling tumor plasticity and normal cell fate. Leveraging human and mouse liver datasets, BAP1 loss in normal cells resulted in lower BAP1 activity scores and lower scores were associated with a less-differentiated phenotype in embryonic cells. Together, our expanded BAP1 mutant samples revealed a transcriptional signature in cancer cells, supporting BAP1's influences on cellular plasticity and cell identity maintenance.

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CiteScore
6.90
自引率
0.00%
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审稿时长
13 weeks
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