Saito Motonobu, Fujiwara Yutaka, Asao Tetsuhiko, Honda Takayuki, Shimada Yoko, Kanai Yae, Tsuta Koji, Kono Koji, Watanabe Shunichi, Ohe Yuichiro, Kohno Takashi
Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
Carcinogenesis. 2017 Oct 26;38(11):1084-1091. doi: 10.1093/carcin/bgx094.
Thymic carcinoma (TC) is a rare cancer whose genomic features have been examined in only a limited number of patients of European descent. Here, we characterized both genomic and epigenomic aberrations by whole exome sequencing, RNA sequencing, methylation array and copy number analyses in TCs from Asian patients and compared them with those in TCs from USA/European patients. Samples analyzed were 10 pairs of snap-frozen surgical specimens of cancerous and non-cancerous thymic tissue. All 10 cases were Japanese patients treated at the National Cancer Center Hospital, Japan, between 1994 and 2010. Mutational signature analysis indicated that the accumulation of age-related mutations drive TC development. We identified recurrent somatic mutations in TET2, CYLD, SETD2, TP53, FBXW7, HRAS and RB1, and no mutations in GTF2I, supporting the hypothesis that TC and thymoma are distinguishable by their genetic profiles. TCs with TET2 mutations had more hypermethylated genes than those without, and hyper-methylation was associated with downregulation of gene expression. Focal genome copy number gains, associated with elevated gene expression, were observed at the KIT (which is known to drive thymic carcinogenesis) and AHNAK2 gene loci. Taken together, the results suggest that the molecular processes leading to TC depend on the accumulation of genetic and epigenetic aberrations. In addition, epigenetic dysregulation as a result of the TET2 mutation was observed in a subset of TCs.
胸腺癌（TC）是一种罕见的癌症，其基因组特征仅在少数欧洲血统患者中进行过研究。在此，我们通过全外显子组测序、RNA测序、甲基化阵列和拷贝数分析，对亚洲患者胸腺癌的基因组和表观基因组畸变进行了特征分析，并将其与美国/欧洲患者胸腺癌的畸变情况进行了比较。分析的样本为10对癌性和非癌性胸腺组织的速冻手术标本。所有10例均为1994年至2010年间在日本国立癌症中心医院接受治疗的日本患者。突变特征分析表明，与年龄相关的突变积累驱动了胸腺癌的发生。我们在TET2、CYLD、SETD2、TP53、FBXW7、HRAS和RB1中鉴定出复发性体细胞突变，而在GTF2I中未发现突变，这支持了胸腺癌和胸腺瘤可通过其基因谱进行区分的假说。与无TET2突变的胸腺癌相比，有TET2突变的胸腺癌有更多的高甲基化基因，且高甲基化与基因表达下调相关。在KIT（已知可驱动胸腺致癌作用）和AHNAK2基因位点观察到与基因表达升高相关的局灶性基因组拷贝数增加。综上所述，结果表明导致胸腺癌的分子过程取决于遗传和表观遗传畸变的积累。此外，在一部分胸腺癌中观察到了由TET2突变导致的表观遗传失调。
