Morishita Asahiro, Iwama Hisakazu, Fujihara Shintaro, Watanabe Miwako, Fujita Koji, Tadokoro Tomoko, Ohura Kyoko, Chiyo Taiga, Sakamoto Teppei, Mimura Shima, Nomura Takako, Tani Joji, Yoneyama Hirohito, Okano Keiichi, Suzuki Yasuyuki, Himoto Takashi, Masaki Tsutomu
Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki, Kagawa 761-0793, Japan.
Life Science Research Center, Kagawa University School of Medicine, Miki, Kagawa 761-0793, Japan.
Oncol Lett. 2018 Jan;15(1):528-532. doi: 10.3892/ol.2017.7334. Epub 2017 Nov 2.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Although the clinical success rate for the treatment of early-stage HCC has improved, the prognosis of advanced HCC remains poor owing to the high recurrence rate and the refractory nature of HCC for various anticancer drugs. A better understanding of the pathogenesis of HCC is therefore critically needed in order to treat HCC, including its genetic alterations. Next-generation sequencing (NGS) has provided an unbiased platform to systematically identify gene mutations and reveal the pathogenesis of various cancers. In the present study, a total of 118 samples (59 liver tissues including cancer and adjacent normal tissues) were sequenced using the AmpliSeq Hotspot Cancer Panel (version 2). The most common somatic mutations identified were tumor protein 53 (; 35.6%) and β-catenin 1 (; 30.5%), and the most frequent variants of those genes were missense variants. In addition, somatic mutations including those in genes encoding colony-stimulating factor 1 receptor (5.1%), epidermal growth factor receptor (6.8%), proto-oncogene (3.4%), Erb-B2 receptor tyrosine kinase 4 (; 1.7%) and serine/threonine kinase 11 (, also known as liver kinase B1; 6.8%) were also identified at a low frequency in patients with HCC. A frameshift variant in , a splice acceptor variant in , a splice region variant in and a stop-gained variant in were also specifically determined. The most abundant alteration was a C:G>T:A transition (50%) and other transversions, i.e., C:G>G:C (19.6%), T:A>C:G (19.6%), C:G>A:T (12.5%), T:A>G:C (12.5%) and T:A>A:T (5.4%). This spectrum pattern differs from that in other solid tumors. mutations in the tumors at advanced stages were significantly more frequent compared with those in early-stage tumors. Additionally, age (<70 vs. ≥70 years) was significantly associated with mutations. Using NGS, a number of novel gene mutations were identified in HCC, including established mutations and disproved mutations. The results of the present study offer new insight and improved understanding of the etiology and the development of HCC.
肝细胞癌（HCC）是全球癌症死亡的第三大主要原因。尽管早期HCC的临床治疗成功率有所提高，但由于高复发率以及HCC对各种抗癌药物的难治性，晚期HCC的预后仍然很差。因此，为了治疗HCC，包括了解其基因改变，迫切需要更好地了解HCC的发病机制。下一代测序（NGS）提供了一个无偏见的平台，可系统地鉴定基因突变并揭示各种癌症的发病机制。在本研究中，使用AmpliSeq热点癌症检测板（第2版）对总共118个样本（59个肝脏组织，包括癌组织和相邻正常组织）进行了测序。鉴定出的最常见体细胞突变是肿瘤蛋白53（；35.6%）和β-连环蛋白1（；30.5%），这些基因最常见的变异是错义变异。此外，在HCC患者中还低频率鉴定出体细胞突变，包括编码集落刺激因子1受体（5.1%）、表皮生长因子受体（6.8%）、原癌基因（3.4%）、埃博拉病毒B2受体酪氨酸激酶4（；1.7%）和丝氨酸/苏氨酸激酶11（，也称为肝激酶B1；6.8%）的基因中的突变。还特异性确定了中的移码变异、中的剪接受体变异、中的剪接区域变异和中的截短变异。最丰富的改变是C:G>T:A转换（50%）以及其他颠换，即C:G>G:C（19.6%）、T:A>C:G（19.6%）、C:G>A:T（12.5%）、T:A>G:C（12.5%）和T:A>A:T（5.4%）。这种谱型模式与其他实体瘤不同。晚期肿瘤中的突变明显比早期肿瘤中的突变更频繁。此外，年龄（<70岁与≥70岁）与突变显著相关。使用NGS，在HCC中鉴定出许多新的基因突变，包括已确定的突变和未证实的突变。本研究结果为HCC的病因和发展提供了新的见解并增进了理解。
