晚期恶性肿瘤基因突变状态二代测序临床意义分析

Clinical significance of next-generation sequencing for advanced cancer

目的靶向治疗是晚期恶性肿瘤的重要治疗方法,二代测序能够准确、高通量地检测基因突变情况,对恶性肿瘤治疗有重要意义。本研究运用二代基因测序(next-generation sequencing,NGS)技术检测晚期恶性肿瘤的基因突变情况,并初步分析错义突变的临床意义。方法 2011-09-01-2016-09-30收集陕西省人民医院肿瘤内科93例晚期恶性肿瘤患者病理组织石蜡标本,利用离子个体化基因检测仪(Ion Personal Genome Machine,Ion Torrent PGM)平台检测标本16个肿瘤相关基因428个常见的突变位点的突变状态,并查询临床试验(Clinical Trails)与美国食品与药物管理局(Food and Drug Administration,FDA)官网数据资料。结果共发现119个错义突变,其中TP53发生频率最高为34.5%(41/119);除TP53突变在各瘤种中均占较大比例外,肺癌突变频率最高为表皮生长因子受体(epidermal growth factor receptor,EGFR)25.7%(9/35),结直肠癌为KRAS 31.6%(6/19),胃癌为KDR 3/6,卵巢癌为KRAS 2/7,宫颈癌为KDR 3/5。70例(75.3%,70/93)检测发现>1个的错义突变位点;93.8%(15/16)的被检测基因有正在研发中的小分子抑制剂和(或)单抗类制剂,75.0%(12/16)的被检测基因已有FDA批准用于特定瘤种的靶向药物,68.8%(11/16)的被检测基因有尚未被FDA批准的靶向药物。结论晚期恶性肿瘤基因错义突变发生率较高,且不同瘤种的突变谱不同,目前基于NGS指导的恶性肿瘤个体化靶向治疗有广阔的应用前景。

OBJECTIVE Target therapy plays a impartment role in the treatment of advanced cancer, and next-gen- eration sequercing could detect gene mutation. This study aimed to detect the paraffin tissue samples of advanced cancer utilizing next-generation sequencing platform, and discuss the related clinical significance. METHODS The paraffin tis- sue samples of 93 cases with advanced cancer were collected in the Department of Medical Oncology, Shanxi Province Peo- ple＇s Hospital between 2011-9-1 and 2016-9-30, We detected 428 common mutation sites of 16 cancer related genes by Ion Torrent PGM platform, and searched information on the official website of the ClinicalTrails and FDA. RESULTS We found 119 missense mutation sites. TP53 was the most common missense mutation site. In addition to TP53, the most common missense mutation site in lung cancer, colorectal cancer, gastric cancer, ovarian cancer and cervical cancer were EGFR（25.7%,9/35）, KRAS（31.6%,6/19）, KDR（3/6）, KRAS（2/7） and KDR（3/5）, respectively. 70 cases（75.3%, 70/93） had one or more missense mutation site, 93.8% （15/16） of the tested genes had small molecular inhibitor or monoeolonal antibodies which were developing, 75.0% （12/16） of the tested genes had the target drugs which had been approved by FDA for specific cancer, and 68.8% （11/16） of the tested genes had target drugs which had not been ap- proved. CONCLUSIONS The frequency of missense mutation in advanced cancer is high, and the mutation pattern is different in different cancer. For advanced cancer, individual target therapy based on the next-generation sequencing has broad prospects.