Genomic analysis of low-grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities
Genomic analysis of low-grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities
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DOI：
10.1002/path.5545
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发表时间：
2020-10-28
影响因子：
7.3
通讯作者：
Campbell, Ian G.
中科院分区：
文献类型：
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作者：
Cheasley, Dane;Nigam, Abhimanyu;Campbell, Ian G.
低级别浆液性卵巢癌（LGSOC）与现有化疗反应差相关，强调需要进行全面的基因组分析并确定新的治疗脆弱性。本文提供的数据代表了迄今为止最大规模的lgsoc遗传研究（n = 71），分析了来自全外显子组测序队列的127个候选基因，以生成突变和拷贝数变异数据。此外，对LGSOC队列进行免疫组化，评估雌激素受体、孕激素受体、TP53和CDKN2A状态。靶向测序确定了47%的RAS/RAF关键通路基因（KRAS， BRAF和NRAS）突变病例，以及推定的新型驱动基因突变，包括USP9X (27%), MACF1 (11%), ARID1A (9%), NF2 (4%), DOT1L（6%）和ASH1L（4%）。免疫组织化学评估显示频繁的雌激素/孕激素受体阳性（85%），同时伴有CDKN2A蛋白缺失（10%）和CDKN2A蛋白过表达（6%），这与较短的疾病结局有关。事实上，90%的LGSOC样本至少含有一种潜在的可操作的改变，其中19/71（27%）的病例预测了标准治疗的临床获益，无论是在另一种癌症适应症中还是在LGSOC特异性中。此外，我们验证了泛素特异性蛋白酶9X (USP9X)，这是染色体x连锁底物特异性去泛素酶和肿瘤抑制因子，作为LGSOC的相关治疗靶点。我们全面的基因组研究强调，有一种对有限数量的独特“驱动”畸变的成瘾，可以转化为改进的治疗途径。(c) 2020大不列颠和爱尔兰病理学会。约翰·威利父子有限公司出版。
Low-grade serous ovarian carcinoma (LGSOC) is associated with a poor response to existing chemotherapy, highlighting the need to perform comprehensive genomic analysis and identify new therapeutic vulnerabilities. The data presented here represent the largest genetic study of LGSOCs to date (n = 71), analysing 127 candidate genes derived from whole exome sequencing cohorts to generate mutation and copy-number variation data. Additionally, immunohistochemistry was performed on our LGSOC cohort assessing oestrogen receptor, progesterone receptor, TP53, and CDKN2A status. Targeted sequencing identified 47% of cases with mutations in key RAS/RAF pathway genes (KRAS, BRAF, and NRAS), as well as mutations in putative novel driver genes including USP9X (27%), MACF1 (11%), ARID1A (9%), NF2 (4%), DOT1L (6%), and ASH1L (4%). Immunohistochemistry evaluation revealed frequent oestrogen/progesterone receptor positivity (85%), along with CDKN2A protein loss (10%) and CDKN2A protein overexpression (6%), which were linked to shorter disease outcomes. Indeed, 90% of LGSOC samples harboured at least one potentially actionable alteration, which in 19/71 (27%) cases were predictive of clinical benefit from a standard treatment, either in another cancer's indication or in LGSOC specifically. In addition, we validated ubiquitin-specific protease 9X (USP9X), which is a chromosome X-linked substrate-specific deubiquitinase and tumour suppressor, as a relevant therapeutic target for LGSOC. Our comprehensive genomic study highlighted that there is an addiction to a limited number of unique 'driver' aberrations that could be translated into improved therapeutic paths. (c) 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.