Nuclear β-catenin localization and mutation of the CTNNB1 gene: a context-dependent association.
Nuclear β-catenin localization and mutation of the CTNNB1 gene: a context-dependent association.
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DOI：
10.1038/s41379-018-0080-0
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Broaddus R
中科院分区：
文献类型：
--
作者：
Kim G;Kurnit KC;Djordjevic B;Singh C;Munsell MF;Wang WL;Lazar AJ;Zhang W;Broaddus R
尽管大多数低级别、早期子宫内膜癌患者仅通过手术即可获得良好的生存率，但复发的患者往往情况不佳。确定可从辅助治疗或更广泛的手术分期中受益的复发高风险患者将有助于优化子宫内膜癌患者的个体化护理。 CTNNB1（编码 β-连环蛋白）突变识别出具有高复发风险的低级别、早期子宫内膜癌患者的子集。 CTNNB1 外显子 3 的突变通常与 β-连环蛋白从膜到细胞核的易位以及 Wnt/β-连环蛋白信号传导的激活有关。鉴于鉴定具有 CTNNB1 突变的子宫内膜癌的临床实用性，本研究的目的是确定免疫组织化学是否可以作为 CTNNB1 基因测序的替代方法。对 345 例子宫内膜癌进行了下一代测序。针对 53/63 CTNNB1 外显子 3 突变肿瘤（其组织可用）和野生型肿瘤的子集确定了 β-连环蛋白的免疫组织化学定位。 β-catenin 的核定位在区分 CTNNB1 突变体和野生型方面具有 100% 的特异性，但敏感性较低 (84.9%)。近一半的 CTNNB1 突变病例只有 5-10% 的肿瘤细胞具有 β-catenin 核定位。对突变状态不知情的病理学家在评估核定位方面的一致性为 100%。 β-连环蛋白核定位的程度与特定的 CTNNB1 基因突变、肿瘤分级、非子宫内膜样成分的存在或肿瘤中特定的并发基因突变无关。相比之下，β-连环蛋白的核定位在硬纤维瘤中更为分散，这种肿瘤也与 CTNNB1 突变相关。因此，通过免疫组织化学评估β-连环蛋白的核定位并不能检测到所有具有 CTNNB1 基因突变的子宫内膜癌。核定位的程度可能依赖于肿瘤类型。对于子宫内膜癌，免疫组织化学可以作为初步筛查，当β-连环蛋白的核定位不存在时，可以使用 CTNNB1 测序。
Although the majority of low grade, early stage endometrial cancer patients have good survival with surgery alone, patients who recur tend to do poorly. Identification of patients at high risk of recurrence who would benefit from adjuvant treatment or more extensive surgical staging would help optimize individualized care of endometrial cancer patients. CTNNB1 (encodes β-catenin) mutations identify a subset of low grade, early stage endometrial cancer patients at high risk of recurrence. Mutation of CTNNB1 exon 3 is classically associated with translocation of the β-catenin protein from the membrane to the nucleus and activation of Wnt/β-catenin signaling. Given the clinical utility of identifying endometrial carcinomas with CTNNB1 mutation, the purpose of this study was to determine if immunohistochemistry could act as a surrogate for CTNNB1 gene sequencing. Next-generation sequencing was performed on 345 endometrial carcinomas. Immunohistochemical localization of β-catenin was determined for 53/63 CTNNB1 exon 3 mutant tumors for which tissue was available and a subset of wildtype tumors. Nuclear localization of β-catenin had 100% specificity in distinguishing CTNNB1 mutant from wildtype, but sensitivity was lower (84.9%). Nearly half of CTNNB1 mutant cases had only 5–10% of tumor cells with β-catenin nuclear localization. The concordance between pathologists blinded to mutation status in assessing nuclear localization was 100%. Extent of β-catenin nuclear localization was not associated with specific CTNNB1 gene mutation, tumor grade, presence of non-endometrioid component, or specific concurrent gene mutations in the tumor. For comparison, nuclear localization of β-catenin was more diffuse in desmoid fibromatosis, a tumor also associated with CTNNB1 mutation. Thus, nuclear localization of β-catenin assessed by immunohistochemistry does not detect all endometrial cancers with CTNNB1 gene mutation. Extent of nuclear localization may be tumor-type dependent. For endometrial cancer, immunohistochemistry could be an initial screen, with CTNNB1 sequencing employed when nuclear localization of β-catenin is absent.
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影响因子：
10.3
作者：
Liu, Yuexin;Patel, Lalit;Zhang, Wei
通讯作者：
Zhang, Wei
影响因子：
64.5
作者：
Chan, SK;Struhl, G
通讯作者：
Struhl, G
影响因子：
5.7
作者：
Estrella, Jeannelyn S.;Tetzlaff, Michael T.;Broaddus, Russell R.
通讯作者：
Broaddus, Russell R.
影响因子：
3.7
作者：
Jamieson, Cara;Mills, Kate M.;Henderson, Beric R.
通讯作者：
Henderson, Beric R.
通过对实体瘤的深层测序增强了临床可行性。
影响因子：
9.3
作者：
Chen K;Meric-Bernstam F;Zhao H;Zhang Q;Ezzeddine N;Tang LY;Qi Y;Mao Y;Chen T;Chong Z;Zhou W;Zheng X;Johnson A;Aldape KD;Routbort MJ;Luthra R;Kopetz S;Davies MA;de Groot J;Moulder S;Vinod R;Farhangfar CJ;Shaw KM;Mendelsohn J;Mills GB;Eterovic AK
通讯作者：
Eterovic AK