Targeted Molecular and Immunohistochemical Analyses of Endometrial Clear Cell Carcinoma Show that POLE Mutations and DNA Mismatch Repair Protein Deficiencies Are Uncommon
Targeted Molecular and Immunohistochemical Analyses of Endometrial Clear Cell Carcinoma Show that POLE Mutations and DNA Mismatch Repair Protein Deficiencies Are Uncommon
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DOI：
10.1097/pas.0000000000001209
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发表时间：
2019-04-01
影响因子：
5.6
通讯作者：
Kinloch, Mary
中科院分区：
文献类型：
--
作者：
Baniak, Nick;Fadare, Oluwole;Kinloch, Mary
子宫内膜透明细胞癌(ECCC)是一种罕见的组织类型，没有独特的分子改变。最近，ECCC报道了肿瘤基因组图谱的分子亚型。ECCC病例来自11个机构，经形态复习和免疫组织化学检查确诊。用组织芯片免疫组织化学方法检测DNA错配修复(MMR)蛋白、P53和ARID1A的表达。对POL、TP53、KRAS和PIK3CA进行了靶向下一代测序。利用MutationTaster和PolyPhen数据库确定突变的致病性。对于P53，补充使用免疫组织化学和测序的方法来评估P53的状态。在57例中，46例根据形态和免疫组织化学(Napsin A阳性和ER阴性)被认为是典型的ECCC。3例因样本不足而无法完成免疫组织化学分析，6例测序失败，共37例。在37例剩余病例中，6/37例(16%)预测到POLE核酸外切酶区域的致病突变，等位基因频率为10%，但未发现热点突变。无MMR缺陷病例。最常见的基因是TP53(59%，22/37)，其次是KRAS(13%，2/15)和PIK3CA(13%，2/15)。目前的研究是迄今为止报道的最大规模的纯ECCC分子分析。当应用严格的分类标准时，MMR缺失和极点突变的亚型不存在。需要就什么是有害的极突变达成进一步的共识。这些发现支持单独研究组织学/免疫组织化学定义的ECCC，以在未来的研究中确定特征性的分子变化。
Endometrial clear cell carcinoma (ECCC) is an uncommon histotype without unique identified molecular alterations. Recently, The Cancer Genome Atlas molecular subtypes have been reported in ECCC. ECCC cases were collected from 11 institutions with diagnoses confirmed by morphologic review and immunohistochemistry. DNA mismatch repair (MMR) proteins, p53 expression, and ARID1A expression was assessed by immunohistochemistry on tissue microarrays. Targeted next-generation sequencing was completed for POLE, TP53, KRAS, and PIK3CA. Pathogenicity of mutations was determined using MutationTaster and PolyPhen databases. For p53, immunohistochemistry and sequencing were complimentarily used to assess the p53 status. Of 57 cases, 46 were considered prototypical ECCC by morphology and immunohistochemical profile (Napsin A-positive and ER-negative). Three cases were excluded because of insufficient sample for complete immunohistochemical analysis, and 6 had failed sequencing, resulting in 37 cases. Of the 37 remaining cases, 6/37 (16%) had predicted pathogenic mutations in the exonuclease domain of POLE with an allelic frequency >10%; however, no hot-spot mutations were identified. No cases were MMR-deficient. The gene most commonly affected was TP53 (59%, 22/37), followed by KRAS (13%, 2/15) and PIK3CA (13%, 2/15). The current study is the largest molecular analysis of pure ECCC reported to date. When strict classification criteria are applied, MMR-deficient and POLE mutated subtypes are not represented. Further consensus on what represents a deleterious POLE mutations is needed. The findings support separately studying histologically/immunohistochemically defined ECCC to identify characteristic molecular alterations in future studies.