当前对于癌症基因组学的了解仍然存在着偏见，忽略了非编码突变。为了系统地寻找调控性的非编码突变，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性位置的突变更有可能具有功能。为此，我们使用了国际癌症基因组计划的全基因组测序数据，并结合了来自240种哺乳动物的演化约束，来鉴定富含非编码约束突变（NCCMs）的基因，这些突变很可能是调控性的。我们将恶性的髓母细胞瘤（MB）与主要为良性的毛细胞星形细胞瘤（PA）进行了比较，发现两者之间的NCCM频率差异很大，符合恶性癌症往往具有更多突变的事实。在PA中，高NCCM频率只影响到BRAF位点，这是PA中最常见的突变基因。相反，在MB中，有500多个基因具有高水平的NCCMs。有趣的是，MB中的一些带有NCCMs的位点与发病年龄有关，例如年轻的MB患者中的HOXB簇。在成年患者中，NCCMs出现在WASF-2/AHDC1/FGR位点，其中一个NCCM导致SRC激酶FGR表达增加，并且增强MB细胞对SRC激酶抑制剂dasatinib的敏感性。因此，我们的分析指出了不同患者群体中的不同分子通路。这些新发现的潜在候选驱动突变可能有助于MB患者分层，对于未来选择个性化治疗方案也非常有价值。

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.