Difference of molecular alterations in HER2-positive and HER2-negative gastric cancers by whole-genome sequencing analysis.
Difference of molecular alterations in HER2-positive and HER2-negative gastric cancers by whole-genome sequencing analysis.
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全基因组测序分析HER2阳性和HER2阴性胃癌分子改变的差异
DOI：
10.2147/cmar.s172710
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发表时间：
2018
影响因子：
3.3
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Zhou C;Feng X;Yuan F;Ji J;Shi M;Yu Y;Zhu Z;Zhang J
本研究的目的是比较人表皮生长因子受体2（HER 2）阳性（HER 2+）和HER 2阴性（HER 2 −）胃癌患者的分子谱，包括体细胞突变和体细胞拷贝数变异（SCNV）。从15名胃癌患者中收集肿瘤样本，包括10名HER 2+样本和5名HER 2 −样本，这些样本通过免疫组织化学进行诊断。通过Illumina HiSeq PE 150仪器进行全基因组测序，沿着进行体细胞单核苷酸变异（SNV）、体细胞结构变异（SV）和SCNV分析。HER 2+和HER 2 −样本的体细胞SNV平均数和突变谱相似。突变类型以C>T为主。对于体细胞SV，HER 2+样本中染色体内易位（2，850.3 ± 1，260.4 vs 1，157 ±586.6，P=0.015）和大片段插入（1，125.6 ±457.4 vs 500±138.9，P=0.002）的数量高于HER 2 −样本。对于所有样品，赖氨酸甲基转移酶2C（KMT 2C）、ZNF 91、TAF 1和MAP 4基因被鉴定为新的显著突变的驱动基因。KMT 2C基因突变主要在HER 2+样本中检出（7/10），与赖氨酸降解途径相关。SERF 2基因突变在HER 2 −样本（3/5）中比在HER 2+样本（1/10）中更常见。拷贝数增加是两组SCNV的主要类型，SCNV的平均数量相似。在HER 2+样本中，使用GISTIC算法，主要观察到已知驱动基因周期蛋白依赖性激酶12（CDK 12，6/10）和RARA（5/10）的扩增，还观察到其他扩增，包括JUP、GJD 3、KRT 39、CDC 6、RAPGEFL 1、WIPF 2、FAM 65 C、KLF 5、DACH 1和PIBF 1基因。在HER 2 −样本中主要检测到溶质载体家族12成员7（SLC 12 A7，5/5）、TTC 40（4/5）和GALNT 9（4/5）基因的扩增。本研究揭示了HER 2+和HER 2 −胃癌样本之间的基因组景观差异。KMT 2C突变和CDK 12扩增主要在HER 2+胃癌中检测到，而SERF 2突变和SLC 12 A7扩增在HER 2 −胃癌中检测到。
The aim of this study was to compare the molecular profiling, including somatic mutation and somatic copy number variation (SCNV), between human epidermal growth factor receptor 2 (HER2)-positive (HER2+) and HER2-negative (HER2−) gastric cancer patients. Tumor samples were collected from 15 gastric cancer patients, including 10 HER2+ samples and five HER2− samples, which were diagnosed by immunohistochemistry. Whole-genome sequencing was performed by Illumina HiSeq PE150 instrument, along with somatic single nucleotide variant (SNV), somatic structural variation (SV) and SCNV analyses. The average number of somatic SNVs and mutation spectrum were similar between HER2+ and HER2− samples. Transition of C>T was the main type of mutation. For somatic SV, number of intrachromosomal translocation (2,850.3±1,260.4 vs 1,157±586.6, P=0.015) and insertion of large fragment (1,125.6±457.4 vs 500±138.9, P=0.002) in HER2+ samples were higher than those in HER2− samples. For all samples, lysine methyltransferase 2C (KMT2C), ZNF91, TAF1 and MAP4 genes were identified as new significant mutated driver genes. KMT2C gene mutations were mainly detected in HER2+ samples (7/10), which were correlated with the lysine degradation pathway. SERF2 gene mutations were more common in HER2− samples (3/5) than in HER2+ samples (1/10). Copy number gain was the major type of SCNV in both groups, and the average number of SCNVs was similar. In the HER2+ samples, by using the GISTIC algorithm, amplification of known driver genes cyclin-dependent kinase 12 (CDK12, 6/10) and RARA (5/10) was mainly observed, and other amplifications including JUP, GJD3, KRT39, CDC6, RAPGEFL1, WIPF2, FAM65C, KLF5, DACH1 and PIBF1 genes were also observed. Amplifications of solute carrier family 12 member 7 (SLC12A7, 5/5), TTC40 (4/5) and GALNT9 (4/5) genes were mainly detected in HER2− samples. Differences in genomic landscape between HER2+ and HER2− gastric cancer samples were revealed in this study. KMT2C mutation and CDK12 amplification were mainly detected in HER2+ gastric cancer, whereas SERF2 mutation and SLC12A7 amplification were detected in HER2− gastric cancer.