Using evolutionary constraint to define novel candidate driver genes in medulloblastoma.
Using evolutionary constraint to define novel candidate driver genes in medulloblastoma.
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DOI：
10.1073/pnas.2300984120
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发表时间：
2023-08-15
影响因子：
11.1
通讯作者：
Forsberg-Nilsson, Karin
中科院分区：
文献类型：
--
作者：
Roy, Ananya;Sakthikumar, Sharadha;Kozyrev, Sergey V.;Nordin, Jessika;Pensch, Raphaela;Makelainen, Suvi;Pettersson, Mats;Karlsson, Elinor K.;Lindblad-Toh, Kerstin;Forsberg-Nilsson, Karin
癌症驱动基因的鉴定对于理解癌症的生物学和定义治疗靶点是重要的。到目前为止，蛋白质编码突变已被频繁研究，但对调控性非编码突变的了解较少。在这里，我们确定了非编码约束突变（NCCM），是新的候选癌症驱动基因的强预测因子，主要由监管变化定义。我们在儿童和成人患者的不同基因中发现了NCCM。这可能会导致更好的分层髓母细胞瘤的年龄和亚组，并可能改善有针对性的治疗策略。目前的癌症基因组学知识仍然偏向于非编码突变。为了系统地寻找调节性非编码突变，我们评估了基因组中保守位置的突变，假设这些突变比低保守位置的突变更有可能是功能性的。为此，我们使用来自国际癌症基因组联盟的全基因组测序数据，并将其与从240种哺乳动物中推断的进化约束相结合，以识别富含非编码约束突变（NCCM）的基因，这些突变可能是自然界中的调节性突变。我们比较髓母细胞瘤（MB），这是恶性的，毛细胞性星形细胞瘤（PA），主要是良性肿瘤，并发现两者之间的高度不同NCCM的频率，在协议的事实，恶性肿瘤往往有更多的突变。在PA中，高NCCM频率仅影响BRAF基因座，这是PA中最常见的突变基因。相比之下，在MB中，>500个基因具有高水平的NCCM。有趣的是，MB中具有NCCM的几个位点与不同的发病年龄相关，例如年轻MB患者中的HOXB簇。在成人患者中，NCCM发生在，例如，WASF-2/AHDC 1/FGR基因座。其中一种NCCM导致SRC激酶FGR表达增加，并增强MB细胞对达沙替尼（一种SRC激酶抑制剂）的反应性。因此，我们的分析指出了不同患者群体中不同的分子途径。这些新发现的推定候选驱动突变可能有助于MB患者分层，并可能对未来选择个性化治疗方案有价值。
Identification of cancer driver genes is important for understanding the biology of cancer and to define treatment targets. So far, protein-coding mutations have been frequently studied but less is known about regulatory noncoding mutation. Here, we identify noncoding constraint mutations (NCCMs) that are strong predictors of novel candidate cancer driver genes, defined primarily by regulatory changes. We find NCCMs in different genes in children and adult patients. This may lead to better stratification of medulloblastoma by age and subgroup and may improve targeted treatment strategies. Current knowledge of cancer genomics remains biased against noncoding mutations. To systematically search for regulatory noncoding mutations, we assessed mutations in conserved positions in the genome under the assumption that these are more likely to be functional than mutations in positions with low conservation. To this end, we use whole-genome sequencing data from the International Cancer Genome Consortium and combined it with evolutionary constraint inferred from 240 mammals, to identify genes enriched in noncoding constraint mutations (NCCMs), mutations likely to be regulatory in nature. We compare medulloblastoma (MB), which is malignant, to pilocytic astrocytoma (PA), a primarily benign tumor, and find highly different NCCM frequencies between the two, in agreement with the fact that malignant cancers tend to have more mutations. In PA, a high NCCM frequency only affects the BRAF locus, which is the most commonly mutated gene in PA. In contrast, in MB, >500 genes have high levels of NCCMs. Intriguingly, several loci with NCCMs in MB are associated with different ages of onset, such as the HOXB cluster in young MB patients. In adult patients, NCCMs occurred in, e.g., the WASF-2/AHDC1/FGR locus. One of these NCCMs led to increased expression of the SRC kinase FGR and augmented responsiveness of MB cells to dasatinib, a SRC kinase inhibitor. Our analysis thus points to different molecular pathways in different patient groups. These newly identified putative candidate driver mutations may aid in patient stratification in MB and could be valuable for future selection of personalized treatment options.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1038/nrg2810
发表时间：
2010-07
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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影响因子：
64.8
作者：
Zoonomia Consortium
通讯作者：
Zoonomia Consortium
插入和缺失针对人类癌症中的谱系定义基因。
影响因子：
64.5
作者：
Imielinski M;Guo G;Meyerson M
通讯作者：
Meyerson M
DOI：
10.1158/1078-0432.ccr-13-2281
发表时间：
2014-02-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bandopadhayay P;Bergthold G;Nguyen B;Schubert S;Gholamin S;Tang Y;Bolin S;Schumacher SE;Zeid R;Masoud S;Yu F;Vue N;Gibson WJ;Paolella BR;Mitra SS;Cheshier SH;Qi J;Liu KW;Wechsler-Reya R;Weiss WA;Swartling FJ;Kieran MW;Bradner JE;Beroukhim R;Cho YJ
通讯作者：
Cho YJ