Assessing mutant p53 in primary high-grade serous ovarian cancer using immunohistochemistry and massively parallel sequencing.
Assessing mutant p53 in primary high-grade serous ovarian cancer using immunohistochemistry and massively parallel sequencing.
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DOI：
10.1038/srep26191
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发表时间：
2016-05-18
影响因子：
4.6
通讯作者：
Marsh DJ
中科院分区：
文献类型：
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作者：
Cole AJ;Dwight T;Gill AJ;Dickson KA;Zhu Y;Clarkson A;Gard GB;Maidens J;Valmadre S;Clifton-Bligh R;Marsh DJ
肿瘤抑制因子p53在癌症中突变，包括超过96%的高级别浆液性卵巢癌（HGSOC）。突变引起野生型p53功能的丧失，这是由于突变型p53（mutp 53）的异常功能的获得，或mutp 53的缺失至低水平。大规模平行测序（MPS）能够提高异质性肿瘤中体细胞变异检测的准确性。我们使用MPS和免疫组织化学（IHC）检测HGSOC的TP 53突变和p53表达。TP 53基因突变率为94%（68/72），其中62%为错义突变。通过间接免疫组化（IHC）检测，错义突变显示p53含量较高，35%（9/26）的非错义突变也是如此。在62%与非错义突变相关的HGSOC中，通过IHC观察到低p53。大多数野生型TP 53肿瘤（75%，6/8）显示中间p53水平。基于p53 IHC的“低”、“中”或“高”分类，检测TP 53突变的总体灵敏度为99%，特异性为75%。我们建议p53免疫组化可作为HGSOC中TP 53突变的替代标志物;然而，这将导致TP 53野生型和突变型肿瘤比例的错误分类。mutp 53的治疗靶向将需要TP 53突变和mutp 53表达的知识。
The tumour suppressor p53 is mutated in cancer, including over 96% of high-grade serous ovarian cancer (HGSOC). Mutations cause loss of wild-type p53 function due to either gain of abnormal function of mutant p53 (mutp53), or absent to low mutp53. Massively parallel sequencing (MPS) enables increased accuracy of detection of somatic variants in heterogeneous tumours. We used MPS and immunohistochemistry (IHC) to characterise HGSOCs for TP53 mutation and p53 expression. TP53 mutation was identified in 94% (68/72) of HGSOCs, 62% of which were missense. Missense mutations demonstrated high p53 by IHC, as did 35% (9/26) of non-missense mutations. Low p53 was seen by IHC in 62% of HGSOC associated with non-missense mutations. Most wild-type TP53 tumours (75%, 6/8) displayed intermediate p53 levels. The overall sensitivity of detecting a TP53 mutation based on classification as ‘Low’, ‘Intermediate’ or ‘High’ for p53 IHC was 99%, with a specificity of 75%. We suggest p53 IHC can be used as a surrogate marker of TP53 mutation in HGSOC; however, this will result in misclassification of a proportion of TP53 wild-type and mutant tumours. Therapeutic targeting of mutp53 will require knowledge of both TP53 mutations and mutp53 expression.