Characterization and clustering of kinase isoform expression in metastatic melanoma.
Characterization and clustering of kinase isoform expression in metastatic melanoma.
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DOI：
10.1371/journal.pcbi.1010065
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发表时间：
2022-05
影响因子：
4.3
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众所周知，人类基因组的突变在癌症中起到了因果作用。动态组调节许多细胞过程，包括生长、增殖、分化和凋亡。除了异常表达外，癌症驱动基因的异常选择性剪接正受到越来越多的关注，因为它可能导致功能域的丢失或获得，改变激酶的下游影响。目前的研究量化了转移性黑色素瘤细胞相对于原发肿瘤的基因组中基因表达和异构体比率的变化。我们对比了来自癌症基因组图谱(TCGA)的103个原发瘤和367个转移瘤样本中的538个总的激酶和3,040个已知的激酶亚型。我们在123个蛋白激酶(23%)中发现了基因水平差异表达(DE)的有力证据。此外，在468个具有不同亚型的激酶中，60个(13%)的亚型比率(DIR)有显著差异。值得注意的是，DE和DIR几乎没有相关性；例如，尽管DE突出了受体酪氨酸激酶(RTK)的丰富，但DIR发现了非受体酪氨酸激酶(NRTK)的剪接变化。利用外显子连接图谱，我们确定了五个在转移性样本中受欢迎的剪接事件的例子。我们研究了转移性黑色素瘤中SLK亚型之间的细胞凋亡和蛋白定位的差异。我们对异构体表达数据进行分类，并确定与基因组亚型和解剖肿瘤位置相关的亚组。值得注意的是，不同的DE和DIR模式将具有BRAF热点突变的样本和(N/K/H)RAS热点突变的样本分开，后者缺乏有效的激酶抑制剂治疗。Ras突变体中的De主要集中在CMGC激酶(包括细胞周期和剪接调节因子)，而不是Braf突变体中的RTK。此外，RAS激酶亚群中的异构体显示出对肿瘤相关过程的丰富，如血管生成和细胞迁移。我们的结果揭示了一种新的治疗靶点识别方法，并展示了不同突变亚型如何对突出癌症中可能的新驱动事件的治疗做出不同的反应。黑色素瘤的发病率在全球范围内持续上升，尤其是在年轻人中。转移性黑色素瘤很难用目前的药物治疗，可能会在几个月内导致患者死亡。激酶抑制剂(Ki)药物在治疗带有BRAFV600E突变的黑色素瘤方面已显示出成功，更好地了解黑色素瘤如何改变人类基因组可能会揭示新的药物靶点。我们使用两种方法：发现基因表达改变的激酶和发现异常选择性剪接的激酶，这方面的研究较少。选择性剪接是一种机制，通过这种机制，一个基因可以产生不同的基因产物(异构体)，即使整个基因的表达没有改变。我们发现了多个异常剪接的例子，并讨论了它们在推动癌症中的可能作用。由于缺乏BRAF突变的黑色素瘤细胞对当前的KIS反应不佳，我们还比较了黑色素瘤基因组亚型之间的结果。特别是，具有原发NRAS突变的样本具有不同的表达模式。我们的结果鼓舞了肿瘤学家未来的研究兴趣，也将对研究其他疾病中异常剪接的研究人员感兴趣。此外，我们还提供了新的算法，用于对同一基因座产生的转录本的改变的异构体组成进行统计测试。
Mutations to the human kinome are known to play causal roles in cancer. The kinome regulates numerous cell processes including growth, proliferation, differentiation, and apoptosis. In addition to aberrant expression, aberrant alternative splicing of cancer-driver genes is receiving increased attention as it could lead to loss or gain of functional domains, altering a kinase’s downstream impact. The present study quantifies changes in gene expression and isoform ratios in the kinome of metastatic melanoma cells relative to primary tumors. We contrast 538 total kinases and 3,040 known kinase isoforms between 103 primary tumor and 367 metastatic samples from The Cancer Genome Atlas (TCGA). We find strong evidence of differential expression (DE) at the gene level in 123 kinases (23%). Additionally, of the 468 kinases with alternative isoforms, 60 (13%) had significant difference in isoform ratios (DIR). Notably, DE and DIR have little correlation; for instance, although DE highlights enrichment in receptor tyrosine kinases (RTKs), DIR identifies altered splicing in non-receptor tyrosine kinases (nRTKs). Using exon junction mapping, we identify five examples of splicing events favored in metastatic samples. We demonstrate differential apoptosis and protein localization between SLK isoforms in metastatic melanoma. We cluster isoform expression data and identify subgroups that correlate with genomic subtypes and anatomic tumor locations. Notably, distinct DE and DIR patterns separate samples with BRAF hotspot mutations and (N/K/H)RAS hotspot mutations, the latter of which lacks effective kinase inhibitor treatments. DE in RAS mutants concentrates in CMGC kinases (a group including cell cycle and splicing regulators) rather than RTKs as in BRAF mutants. Furthermore, isoforms in the RAS kinase subgroup show enrichment for cancer-related processes such as angiogenesis and cell migration. Our results reveal a new approach to therapeutic target identification and demonstrate how different mutational subtypes may respond differently to treatments highlighting possible new driver events in cancer. The incidence of melanoma continues to rise worldwide, especially in young adult populations. Metastasized melanoma is difficult to treat with current drugs and may kill patients in a matter of months. Kinase inhibitor (KI) drugs have shown success in treating melanoma with BRAFV600E mutations, and a better understanding of how melanoma alters the human kinome may reveal new drug targets. We use two approaches: finding kinases with altered gene expression and finding kinases with aberrant alternative splicing, which is less studied. Alternative splicing is a mechanism through which a gene may produce different gene products (isoforms), even if overall gene expression does not change. We find multiple examples of aberrant splicing and discuss their possible role in driving cancer. Because melanoma cells lacking a BRAF mutation do not respond well to current KIs, we also contrast results between genomic subtypes of melanomas. In particular, samples with a primary NRAS mutation have distinct expression patterns. Our results buoy future research interests of oncologists; and will also be of interest to researchers studying aberrant splicing in other diseases. Additionally, we provide novel algorithms for statistical testing of altered isoform makeup of transcripts generated from the same gene locus.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
37.3
作者：
Du Z;Lovly CM
通讯作者：
Lovly CM
影响因子：
30.8
作者：
Harbour, J. William;Roberson, Elisha D. O.;Anbunathan, Hima;Onken, Michael D.;Worley, Lori A.;Bowcock, Anne M.
通讯作者：
Bowcock, Anne M.
影响因子：
78.5
作者：
Fleuren, Emmy D. G.;Zhang, Luxi;Daly, Roger J.
通讯作者：
Daly, Roger J.
影响因子：
4.3
作者：
Chen, Yun-Ching;Elnitski, Laura
通讯作者：
Elnitski, Laura