BACKGROUND An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance. METHODS The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development. RESULTS Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors. CONCLUSIONS Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.

中文翻译：

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实体瘤样品中潜在可操作的体细胞致癌突变的鉴定及其临床影响。

背景技术越来越多的抗癌治疗剂靶向由许多不同肿瘤类型表达的特异性突变蛋白。这些疗法的成功使用取决于患者肿瘤内是否存在可以赋予临床效力或耐药性的体细胞突变。方法我们研究的目的是确定多个疾病位点中47个与癌症相关的基因中潜在可靶向的复发性体细胞热点突变的类型，频率，重叠和功能蛋白质组学效应，这些可能是使用当前可用的药物或临床药物作为潜在治疗靶标发展。结果使用MassArray技术分析的1300例患者中，有571个（43.9％）肿瘤具有至少一种体细胞突变。在30个不同的基因中鉴定出突变。KRAS（16.5％），PIK3CA（13。6％）和BRAF（3.8％）是最常见的突变基因。前列腺癌（10.8％）的体细胞突变数最少，而肉瘤中没有突变。眼黑素瘤（90.6％），子宫内膜癌（72.4％）和结直肠癌（66.4％）具有最高的突变数。我们注意到肿瘤不同部位的突变（94％）与匹配的原发和转移样品（90％）之间的高度一致性。KRAS和BRAF突变是互斥的。突变共现主要涉及PIK3CA和PTPN11，以及PTPN11和APC。反相蛋白质阵列（RPPA）分析表明，与野生型肿瘤相比，具有突变的肿瘤中PI3K和MAPK信号通路的变化更大。结论热点突变分析是一种敏感的，