Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10^Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.

子宫内膜癌仍然是一个公共健康问题，其发病率不断上升，特别是在年轻女性中。保留生育能力是治疗早发性子宫内膜样子宫内膜癌 (EEEC) 的一个重要考虑因素，特别是对于 40 岁以下保持生育愿望和能力的患者。为了阐明 EEEC 的分子特征，我们对 215 名子宫内膜癌患者（其中 81 名患有 EEEC）进行了大规模多组学研究。我们揭示了暴露体相关突变特征与 EEEC 之间的意外关联，其特征是特定的CTNNB1和SIGLEC10热点突变以及下游通路的破坏。有趣的是， EEEC 中的SIGLEC10 ^Q144K突变导致 SIGLEC-10 蛋白表达异常，并通过与雌激素受体 α 相互作用促进孕激素抵抗。我们还确定了 EEEC 保留生育治疗中孕激素反应的潜在蛋白质生物标志物。总的来说，我们的研究建立了 EEEC 的蛋白质基因组资源，揭示了暴露组和基因组敏感性之间的相互作用，有助于制定 EEEC 的一级预防和早期检测策略。