Introduction Endometrial carcinoma (EC) remains a public health concern with a growing incidence particularly in younger women. Women with early-onset endometrioid EC (EEEC) who wish to maintain fertility are a worldwide concern, and biomarkers for predicting which patients will respond to progestin-based fertility-sparing therapy are a major unmet clinical need.

Methods To comprehensively characterize the proteogenomic characteristics of the early-onset endometroid endometrial carcinoma (EEEC), we conducted a multi-omics study (genomics, and proteomics) with FFPE tissues from paired tumor and normal tissues of 222 endometrioid ECs (including 81 EEECs younger than 40 who mainly received fertility-sparing treatment ) and 14 atypical endometrial hyperplasia (AEH) patients from Tongji and Fudan Hospital (TJFD cohort) in China.

Results EEEC was featured by exclusive germline muataions,a higher BMI and downstream dysregualted lipid metabolism signaling. Our integrated multi-omics analysis unexpectedly revealed an exposome-related mutational signature to be associated with EEEC leading to EEEC specific CTNNB1 and SIGLEC10 hotspot mutations and downstream protein pathway disturbance. Interestingly, in EEECs SIGLEC10^Q144K mutation resulted in aberrant Siglec-10 protein expression and promoted progestin resistance by interacting with ERα. We identified and validated four (EEF1E1, ILVBL, SRPK1 and NUDT5) biomarkers of progestin resistance.

Conclusion/Implications Our study provides a unique high-quality proteogenomic resource of EEECs, and explicates the distinct clinical and molecular characteristics of EEECs, encompass-ing obesity, genetic susceptibility, and environmental exposure, that are concomitant with pathogenesis and progestin resistance. Furthermore, we identified biomarkers for progestin response in EEEC fertility-sparing treatment. These attributes can be utilized to promote primary prevention and early detection of EEECs.