Chien Jeremy, Sicotte Hugues, Fan Jian-Bing, Humphray Sean, Cunningham Julie M, Kalli Kimberly R, Oberg Ann L, Hart Steven N, Li Ying, Davila Jaime I, Baheti Saurabh, Wang Chen, Dietmann Sabine, Atkinson Elizabeth J, Asmann Yan W, Bell Debra A, Ota Takayo, Tarabishy Yaman, Kuang Rui, Bibikova Marina, Cheetham R Keira, Grocock Russell J, Swisher Elizabeth M, Peden John, Bentley David, Kocher Jean-Pierre A, Kaufmann Scott H, Hartmann Lynn C, Shridhar Viji, Goode Ellen L
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
Nucleic Acids Res. 2015 Aug 18;43(14):6945-58. doi: 10.1093/nar/gkv111. Epub 2015 Apr 27.
To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis with The Cancer Genome Atlas (TCGA) indicated that low and late stage HGSOCs have similar mutation and copy number profiles. We also found evidence that deleterious TP53 mutations are the earliest events, followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1 or BRCA2. Inactivation of HR appears to be an early event, as 62.5% of tumours showed a LOH pattern suggestive of HR defects. Three tumours with the highest ploidy had little genome-wide LOH, yet one of these had a homozygous somatic frame-shift BRCA2 mutation, suggesting that some carcinomas begin as tetraploid then descend into diploidy accompanied by genome-wide LOH. Lastly, we found evidence that structural variants (SV) cluster in HGSOC, but are absent in one ultramutated tumor, providing insights into the pathogenesis of low stage HGSOC.
为了确定高级别浆液性卵巢癌（HGSOC）早期的体细胞变化，我们对16例低分期HGSOC的罕见样本进行了全基因组测序。大多数样本显示出广泛的结构改变（其中一个具有超突变特征），表现出高水平的p53免疫反应性，并携带TP53突变、缺失或失活。在两个肿瘤中观察到BRCA1和BRCA2突变，九个样本显示出同源重组（HR）缺陷的证据。与癌症基因组图谱（TCGA）的联合分析表明，低分期和晚期HGSOC具有相似的突变和拷贝数特征。我们还发现，有害的TP53突变是最早发生的事件，随后是携带TP53、BRCA1或BRCA2的染色体缺失或杂合性丢失（LOH）。HR失活似乎是一个早期事件，因为62.5%的肿瘤显示出提示HR缺陷的LOH模式。三个倍性最高的肿瘤全基因组LOH较少，但其中一个具有纯合的体细胞移码BRCA2突变，这表明一些癌始于四倍体，然后伴随着全基因组LOH降为二倍体。最后，我们发现证据表明结构变异（SV）在HGSOC中聚集，但在一个超突变肿瘤中不存在，这为低分期HGSOC的发病机制提供了见解。
