抗 HER2 治疗适用于 erb-b2 受体酪氨酸激酶 2 (ERBB2) 扩增/过度表达的子宫内膜癌 (EC)。突变构成了 ERBB2 激活的另一种模式，但仅报道了罕见的 ERBB2 突变 EC。我们试图描述 ERBB2 突变 EC 的临床病理学和遗传特征。从接受临床肿瘤正常组测序的 2638 个 EC 的机构队列中，鉴定出 69 个 (2.6%) 具有致病性 ERBB2 突变，其中 11 个也有 ERBB2 扩增。最常见的 ERBB2 热点突变是 V842I (38%) 和 R678Q (25%)。 87% 的可评估病例中 ERBB2 突变是克隆性的。免疫组织化学显示，大多数 ERBB2 突变 EC 中 HER2 蛋白表达较低（66% 为 0/1，27% 为 2）；所有 3 个肿瘤 (7.3%) 也均出现 ERBB2 扩增。与 ERBB2 野生型 EC（有或没有 ERBB2 扩增）相比，ERBB2 突变/非扩增 EC 富集了微卫星不稳定性高 (MSI-H)，并且在较小程度上富集了 DNA 聚合酶 epsilon、催化亚基 (POLE) ）分子亚型，并与高肿瘤突变负荷和低染色体不稳定性相关。 ERBB2 突变/非扩增患者与野生型 EC 患者的生存结果相似，而单变量而非多变量分析显示 ERBB2 扩增与较差的预后相关。总之，ERBB2 突变定义了一个罕见的 EC 亚组，其致病性不同于 ERBB2 野生型和 ERBB2 扩增 EC。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Anti-HER2 therapy is indicated for erb-b2 receptor tyrosine kinase 2 (ERBB2)-amplified/overexpressing endometrial carcinoma (EC). Mutations constitute another mode of ERBB2 activation, but only rare ERBB2-mutated ECs have been reported. We sought to characterize the clinicopathologic and genetic features of ERBB2-mutated EC. From an institutional cohort of 2638 ECs subjected to clinical tumor-normal panel sequencing, 69 (2.6%) with pathogenic ERBB2 mutation(s) were identified, of which 11 were also ERBB2-amplified. The most frequent ERBB2 hotspot mutations were V842I (38%) and R678Q (25%). ERBB2 mutations were clonal in 87% of evaluable cases. Immunohistochemistry revealed low HER2 protein expression in most ERBB2-mutated ECs (0/1+ in 66%, 2+ in 27%); all 3+ tumors (7.3%) were also ERBB2-amplified. Compared to ERBB2-wildtype ECs (with or without ERBB2 amplification), ERBB2-mutated/non-amplified ECs were enriched for the microsatellite instability-high (MSI-H) and, to a lesser extent, DNA polymerase epsilon, catalytic subunit (POLE) molecular subtypes, and associated with high tumor mutational burden and low chromosomal instability. Survival outcomes were similar between patients with ERBB2-mutated/non-amplified versus wildtype EC, whereas ERBB2 amplification was associated with worse prognosis on univariate, but not multivariate, analyses. In conclusion, ERBB2 mutation defines a rare subgroup of ECs that is pathogenically distinct from ERBB2-wildtype and ERBB2-amplified ECs.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.