Genomic characterization of Chinese ovarian clear cell carcinoma identification driver genes by whole exome sequencing
Genomic characterization of Chinese ovarian clear cell carcinoma identification driver genes by whole exome sequencing
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全外显子组测序对中国卵巢透明细胞癌识别驱动基因的基因组表征
DOI：
10.1016/j.neo.2020.06.002
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发表时间：
2020-09-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Rong
中科院分区：
文献类型：
--
作者：
Yang, Qin;Zhang, Cancan;Zhang, Rong
卵巢透明细胞癌（OCCC）的遗传学特征尚不清楚。我们的目的是确定这种类型癌症中的靶向基因组改变。通过全外显子组测序（WES）分析了42份OCCC福尔马林固定、石蜡包埋（FFPE）组织样本，并对74份FFPE组织样本进行了靶向测序（TS）以确认相关驱动突变。通过细胞计数试剂盒-8（CCK 8）测定评估细胞增殖。在42个样本中，ARID1A（64.3%）和PIK3CA（28.5%）经常发生突变，PPP2R1A（11.9%），PTEN（7.1%）和KRAS（4.8%）也是如此，这些在以前的OCCC研究中已经报道过。我们还检测到MUC4（28.6%），MAGEE1（19%）和ARID3A（16.7%）的突变;与这些基因的关联以前没有报道过。在83%的OCCCs中，功能性蛋白激活途径与增殖和存活相关（包括PI3K/AKT、TP53和ERBB2途径），在71%的OCCCs中与染色质重塑相关。MAGEE1发生改变的患者（靶向测序队列中为64%）的临床结局较差（对数秩p <0.05）。功能研究表明，两个MAGEE1突变体，一个缺乏两个法师结构域，另一个含有两个法师结构域，显着降低OCCC细胞的增殖能力。我们使用全外显子组测序和OCCC患者样本的靶向测序成功鉴定了OCCC中的新遗传改变以及治疗这种恶性肿瘤的潜在治疗靶点。
Little is known about the genetic alterations characteristic of ovarian clear cell carcinoma (OCCC). Our aim was to identify targetable genomic alterations in this type of cancer. Forty-two OCCC formalin-fixed, paraffin-embedded (FFPE) tissue samples were analyzed by whole-exome sequencing (WES), and 74 FFPE tissue samples underwent targeted sequencing (TS) to confirm the relevant driver mutations. Cell proliferation was assessed by cell counting kit-8 (CCK8) assays. In the 42 samples, ARID1A (64.3%) and PIK3CA (28.5%) were frequently mutated, as were PPP2R1A (11.9%), PTEN (7.1%) and KRAS (4.8%), which have been reported in previous OCCC studies. We also detected mutations in MUC4 (28.6%), MAGEE1 (19%), and ARID3A (16.7%); associations with these genes have not been previously reported. The functional protein-activated pathways were associated with proliferation and survival (including the PI3K/AKT, TP53, and ERBB2 pathways) in 83% of OCCCs and with chromatin remodeling in 71% of OCCCs. Patients with alterations in MAGEE1 (64% in the targeted sequencing cohort) had worse clinical outcomes (log-rank p < 0.05). A functional study revealed that two MAGEE1 mutants, one lacking two MAGE domains and the other containing two MAGE domains, significantly decreased the proliferative capacity of OCCC cells. We successfully identified novel genetic alterations in OCCC using whole-exome sequencing and targeted sequencing of OCCC patient samples and potential therapeutic targets for the treatment of this malignancy.