Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling.
Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling.
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DOI：
10.1002/path.4230
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发表时间：
2013-09
影响因子：
7.3
通讯作者：
Shah, Sohrab P.
中科院分区：
文献类型：
--
作者：
Bashashati, Ali;Ha, Gavin;Tone, Alicia;Ding, Jiarui;Prentice, Leah M.;Roth, Andrew;Rosner, Jamie;Shumansky, Karey;Kalloger, Steve;Senz, Janine;Yang, Winnie;McConechy, Melissa;Melnyk, Nataliya;Anglesio, Michael;Luk, Margaret T. Y.;Tse, Kane;Zeng, Thomas;Moore, Richard;Zhao, Yongjun;Marra, Marco A.;Gilks, Blake;Yip, Stephen;Huntsman, David G.;McAlpine, Jessica N.;Shah, Sohrab P.
高级别浆液性卵巢癌（HGSC）的特点是预后差，通常归因于耐药亚克隆的出现。我们试图测量原代未经治疗的HGSC内的基因组多样性程度，以检查治疗前肿瘤演变的自然状态。我们对31例空间和时间上分离的HGSC肿瘤标本（6例患者）进行了外显子组测序、拷贝数分析、靶向扩增子深度测序和基因表达谱分析，包括卵巢肿块、远处转移和输卵管病变。我们发现肿瘤内突变、拷贝数和基因表达谱存在广泛变异，仅在一部分样本中存在关键驱动基因改变（例如PIK 3CA、CTNNB 1、NF 1）。平均而言，在给定病例的每个样品中仅存在51.5%的突变（范围10.2-91.4%），其中TP 53作为唯一的体细胞突变始终存在于所有样品中。复杂的节段性非整倍性，如全基因组加倍，存在于来自同一个体的样品的子集中，具有独立于点突变获取的分离的不同拷贝数变化。进化史的重建显示，1例患者具有混合HGSC和类增生组织学，在输卵管中具有共同的病因起源，随后在组织学上不同的样本中选择不同的驱动突变。在这个病人中，我们观察到混合细胞群在早期输卵管病变，表明多样性出现在肿瘤发生的早期阶段。我们的研究结果表明，HGSC在治疗前表现出高度个体化的进化轨迹和多样化的基因组挂毯，揭示了一个重要的生物学特征，为未来个性化治疗方案的设计和耐药机制的研究提供信息。
High-grade serous ovarian cancer (HGSC) is characterized by poor outcome, often attributed to the emergence of treatment-resistant subclones. We sought to measure the degree of genomic diversity within primary, untreated HGSCs to examine the natural state of tumour evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on 31 spatially and temporally separated HGSC tumour specimens (six patients), including ovarian masses, distant metastases and fallopian tube lesions. We found widespread intratumoural variation in mutation, copy number and gene expression profiles, with key driver alterations in genes present in only a subset of samples (eg PIK3CA, CTNNB1, NF1). On average, only 51.5% of mutations were present in every sample of a given case (range 10.2–91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole-genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology, with common aetiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating that diversity arises at early stages of tumourigenesis. Our results revealed that HGSCs exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug-resistance mechanisms.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1097/pas.0b013e3181dcede7
发表时间：
2010-06
期刊：
The American journal of surgical pathology
影响因子：
--
作者：
Kuhn E;Meeker A;Wang TL;Sehdev AS;Kurman RJ;Shih IeM
通讯作者：
Shih IeM
影响因子：
7.3
作者：
Ahmed, Ashour Ahmed;Etemadmoghadam, Dariush;Temple, Jillian;Lynch, Andy G.;Riad, Mohamed;Sharma, Raghwa;Stewart, Colin;Fereday, Sian;Caldas, Carlos;DeFazio, Anna;Bowtell, David;Brenton, James D.
通讯作者：
Brenton, James D.
影响因子：
8
作者：
Cooke, S. L.;Ng, C. K. Y.;Melnyk, N.;Garcia, M. J.;Hardcastle, T.;Temple, J.;Langdon, S.;Huntsman, D.;Brenton, J. D.
通讯作者：
Brenton, J. D.
影响因子：
4.7
作者：
Losi, L;Baisse, B;Benhattar, J
通讯作者：
Benhattar, J