Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier.
Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier.
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DOI：
10.1186/s13059-014-0526-8
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发表时间：
2014-12-17
期刊：
影响因子：
12.3
通讯作者：
Brenton JD
中科院分区：
文献类型：
--
作者：
Martins FC;Santiago Id;Trinh A;Xian J;Guo A;Sayal K;Jimenez-Linan M;Deen S;Driver K;Mack M;Aslop J;Pharoah PD;Markowetz F;Brenton JD
TP53和BRCA1/2突变是高级别浆液性卵巢癌(HGSOC)的主要诱因。我们假设，结合肿瘤切片图像分析的组织表型和基因组图谱，可以揭示其他重要的驱动因素。对TCGA HGSOC肿瘤间质含量的自动估计结合基因组分析表明，间质对PTEN表达的估计有强烈的偏差。使用包含521例HGSOC的组织芯片，在两个独立的队列中检测了肿瘤特异性PTEN的表达。PTEN缺失或下调发生在免疫荧光法的第一组队列中的77%和免疫组织化学确认组的52%中，在根据研究地点、年龄、分期和分级进行调整的多变量Cox回归模型中，PTEN缺失或下调与较差的生存相关。对TCGA资料的再分析表明，PTEN的半合子缺失是常见的(36%)，PTEN的表达与雄激素受体的表达呈正相关。在TCGA和第一组队列的免疫组织化学分析的数据中，雄激素受体的低表达与生存率降低有关。PTEN缺失是HGSOC中的常见事件，其定义为预后较差的亚组，提示HGSOC应合理使用靶向PI3K和雄激素受体的药物。这项工作表明，将来自图像的组织表型与基因组分析相结合的综合方法可以解决组织异质性的混杂效应，并应用于识别其他癌症的新驱动因素。本文的在线版本(doi：10.1186/s13059-0140526-8)包含补充材料，授权用户可以使用。
TP53 and BRCA1/2 mutations are the main drivers in high-grade serous ovarian carcinoma (HGSOC). We hypothesise that combining tissue phenotypes from image analysis of tumour sections with genomic profiles could reveal other significant driver events. Automatic estimates of stromal content combined with genomic analysis of TCGA HGSOC tumours show that stroma strongly biases estimates of PTEN expression. Tumour-specific PTEN expression was tested in two independent cohorts using tissue microarrays containing 521 cases of HGSOC. PTEN loss or downregulation occurred in 77% of the first cohort by immunofluorescence and 52% of the validation group by immunohistochemistry, and is associated with worse survival in a multivariate Cox-regression model adjusted for study site, age, stage and grade. Reanalysis of TCGA data shows that hemizygous loss of PTEN is common (36%) and expression of PTEN and expression of androgen receptor are positively associated. Low androgen receptor expression was associated with reduced survival in data from TCGA and immunohistochemical analysis of the first cohort. PTEN loss is a common event in HGSOC and defines a subgroup with significantly worse prognosis, suggesting the rational use of drugs to target PI3K and androgen receptor pathways for HGSOC. This work shows that integrative approaches combining tissue phenotypes from images with genomic analysis can resolve confounding effects of tissue heterogeneity and should be used to identify new drivers in other cancers. The online version of this article (doi:10.1186/s13059-014-0526-8) contains supplementary material, which is available to authorized users.
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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：
7.3
作者：
Leinster, D. Andrew;Kulbe, Hagen;Everitt, Gemma;Thompson, Richard;Perretti, Mauro;Gavins, Felicity N. E.;Cooper, Dianne;Gould, David;Ennis, Darren P.;Lockley, Michelle;McNeish, Iain A.;Nourshargh, Sussan;Balkwill, Frances R.
通讯作者：
Balkwill, Frances R.
影响因子：
28.2
作者：
Hanrahan AJ;Schultz N;Westfal ML;Sakr RA;Giri DD;Scarperi S;Janakiraman M;Olvera N;Stevens EV;She QB;Aghajanian C;King TA;Stanchina Ed;Spriggs DR;Heguy A;Taylor BS;Sander C;Rosen N;Levine DA;Solit DB
通讯作者：
Solit DB
影响因子：
82.9
作者：
Dinulescu, DM;Ince, TA;Jacks, T
通讯作者：
Jacks, T
DOI：
10.1073/pnas.201167798
发表时间：
2001-09-25
影响因子：
11.1
作者：
Kwabi-Addo, B;Giri, D;Ittmann, M
通讯作者：
Ittmann, M