Kancherla Venkatesh, Abdullazade Samir, Matter Matthias S, Lanzafame Manuela, Quagliata Luca, Roma Guglielmo, Hoshida Yujin, Terracciano Luigi M, Ng Charlotte K Y, Piscuoglio Salvatore
Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Department of Biology, University of Naples Federico II, Naples, Italy.
Front Genet. 2018 Feb 2;9:2. doi: 10.3389/fgene.2018.00002. eCollection 2018.
The gene is the most commonly mutated gene in human cancers and mutations in have been shown to have either gain-of-function or loss-of-function effects. Using the data generated by The Cancer Genome Atlas, we sought to define the spectrum of mutations in hepatocellular carcinomas (HCCs) and their association with clinicopathologic features, and to determine the oncogenic and mutational signatures in -mutant HCCs. Compared to other cancer types, HCCs harbored distinctive mutation hotspots at V157 and R249, whereas common mutation hotspots in other cancer types, R175 and R273, were extremely rare in HCCs. In terms of clinicopathologic features, in addition to the associations with chronic viral infection and high Edmondson grade, we found that somatic mutations were less frequent in HCCs with cholestasis or tumor infiltrating lymphocytes, but were more frequent in HCCs displaying necrotic areas. An analysis of the oncogenic signatures based on the genetic alterations found in genes recurrently altered in HCCs identified four distinct -mutant subsets, three of which were defined by mutations, 1q amplifications or 8q24 amplifications, respectively, that co-occurred with mutations. We also found that mutational signature 12, a liver cancer-specific signature characterized by T>C substitutions, was prevalent in HCCs with wild-type or with missense mutations, but not in HCCs with deleterious mutations. Finally, whereas patients with HCCs harboring deleterious mutations had worse overall and disease-free survival than patients with -wild-type HCCs, patients with HCCs harboring missense mutations did not have worse prognosis. In conclusion, our results highlight the importance to consider the genetic heterogeneity among -mutant HCCs in studies of biomarkers and molecular characterization of HCCs.
该基因是人类癌症中最常发生突变的基因，其突变已被证明具有功能获得或功能丧失效应。利用癌症基因组图谱生成的数据，我们试图确定肝细胞癌（HCC）中该基因的突变谱及其与临床病理特征的关联，并确定该基因突变型HCC中的致癌和突变特征。与其他癌症类型相比，HCC在V157和R249处有独特的突变热点，而其他癌症类型中的常见突变热点R175和R273在HCC中极为罕见。在临床病理特征方面，除了与慢性病毒感染和高Edmondson分级相关外，我们发现胆汁淤积或肿瘤浸润淋巴细胞的HCC中该基因的体细胞突变较少见，但在有坏死区域的HCC中更常见。基于HCC中反复改变的基因中的遗传改变对致癌特征进行分析，确定了四个不同的该基因突变子集，其中三个分别由该基因突变、1q扩增或8q24扩增定义，它们与该基因突变同时发生。我们还发现，突变特征12，一种以T>C替换为特征的肝癌特异性特征，在野生型该基因或错义该基因突变的HCC中普遍存在，但在有害该基因突变的HCC中不存在。最后，虽然携带有害该基因突变的HCC患者的总生存期和无病生存期比该基因野生型HCC患者差，但携带错义该基因突变的HCC患者的预后并不差。总之，我们的结果强调了在HCC的生物标志物研究和分子特征研究中考虑该基因突变型HCC之间遗传异质性的重要性。
