Multidimensional Molecular Characteristics of Early-Onset Endometrioid Endometrial Carcinoma, And Potential Predictors Of Response To Fertility Sparing Therapy

Abstract 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. To illuminate the molecular characteristics of EEEC, we undertook a large-scale proteogenomic study of 222 EECs encompassing 81 EEEC who were 40 or younger. In contrast to late-onset EEC, 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 SIGLEC10Q144K mutation resulted in aberrant Siglec-10 protein expression and promoted progestin resistance by interacting with ERα. Collectively, our study provides a unique high-quality proteogenomic resource of EEECs while enabling insights into interactions between exposome and genomic susceptibilities for primary prevention and early detection of EEECs. Furthermore, we identified biomarkers for progestin response in EEEC fertility-sparing treatment.