Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response

Nat Genet. 2024 Apr;56(4):637-651. doi: 10.1038/s41588-024-01703-z. Epub 2024 Apr 2.


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, SIGLEC10Q144K 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.

MeSH terms

  • Antineoplastic Agents, Hormonal
  • Carcinoma, Endometrioid* / drug therapy
  • Carcinoma, Endometrioid* / genetics
  • Carcinoma, Endometrioid* / pathology
  • Endometrial Hyperplasia* / drug therapy
  • Endometrial Neoplasms* / drug therapy
  • Endometrial Neoplasms* / genetics
  • Endometrial Neoplasms* / pathology
  • Female
  • Fertility Preservation* / methods
  • Humans
  • Progestins / therapeutic use
  • Proteogenomics*
  • Retrospective Studies


  • Progestins
  • Antineoplastic Agents, Hormonal