Protein Domain-Level Landscape of Cancer-Type-Specific Somatic Mutations

Identifying driver mutations and their functional consequences is critical to our understanding of cancer. Towards this goal, and because domains are the functional units of a protein, we explored the protein domain-level landscape of cancer-type-specific somatic mutations. Specifically, we systematically examined tumor genomes from 21 cancer types to identify domains with high mutational density in specific tissues, the positions of mutational hotspots within these domains, and the functional and structural context where possible. While hotspots corresponding to specific gain-of-function mutations are expected for oncoproteins, we found that tumor suppressor proteins also exhibit strong biases toward being mutated in particular domains. Within domains, however, we observed the expected patterns of mutation, with recurrently mutated positions for oncogenes and evenly distributed mutations for tumor suppressors. For example, we identified both known and new endometrial cancer hotspots in the tyrosine kinase domain of the FGFR2 protein, one of which is also a hotspot in breast cancer, and found new two hotspots in the Immunoglobulin I-set domain in colon cancer. Thus, to prioritize cancer mutations for further functional studies aimed at more precise cancer treatments, we have systematically correlated mutations and cancer types at the protein domain level.鉴定驱动突变及其功能效应，对于我们深入理解癌症的发生机制至关重要。基于此研究目标，且鉴于蛋白质结构域（protein domain）是蛋白质的功能基本单元，我们针对癌症类型特异性体细胞突变（somatic mutation）开展了蛋白质结构域层面的全景分析。具体而言，我们系统分析了21种癌症类型的肿瘤基因组，旨在识别特定组织中突变密度较高的结构域、这些结构域内的突变热点（mutational hotspot）位置，并尽可能明确其功能与结构背景。尽管癌蛋白（oncoprotein）的突变热点通常对应特定的功能获得性突变（gain-of-function mutation），但我们发现肿瘤抑制蛋白（tumor suppressor protein）同样存在显著的特定结构域突变偏好性。然而在结构域内部，我们观察到了预期的突变模式：致癌基因（oncogene）存在反复突变的位点，而肿瘤抑制基因的突变则呈均匀分布。举例而言，我们在FGFR2蛋白的酪氨酸激酶结构域（tyrosine kinase domain）中发现了子宫内膜癌的已知与全新突变热点，其中一个同时也是乳腺癌的突变热点；此外在结肠癌的免疫球蛋白I-set结构域（Immunoglobulin I-set domain）中发现了两处全新的突变热点。因此，为了筛选出可用于后续功能研究、以实现更精准癌症治疗的癌症相关突变，我们在蛋白质结构域层面系统关联了突变与癌症类型的对应关系。