ABSTRACT Around 10% of reproductive-age women have endometriosis, although prevalence is thought to differ by ancestry, with rates the highest in Asians where around 15% of women are affected. The molecular drivers of this common chronic gynecologic condition are poorly understood, particularly in non-Whites. Endometriosis is a major cause of pain and infertility in women, is associated with significant financial burden, and multiple comorbidities including pain syndromes, inflammatory and immune conditions, anxiety, and depression. Endometriosis lesions frequently harbor somatic mutations in “driver” genes such as KRAS, PIK3CA and ARID1A, but the consequences of these mutations are poorly understood. The goal of this proposal is to leverage a deeply annotated collection of specimens from >1,400 endometriosis patients to catalogue the spectrum of of somatic mutations in endometriosis across White, Asian, Black and Hispanic Women and to use state-of-the-art single cell and spatial genomics technologies to identify therapeutic opportunities associated with specific mutations. Aim 1 will use exome and targeted sequencing to map population-specific frequencies of somatic drivers. Aim 2 will profile endometriosis and eutopic endometrium tissues using single cell transcriptomic and epigenomic analyses and spatial transcriptomics to map the cellular and molecular impacts of somatic mutations to identify therapeutic targets. Aim 3 will use an orthotopic syngeneic mouse model of endometriosis to validate the mechanisms by which mutations impact endometriosis formation and persistence and to test therapeutics tailored to the genetic alterations in the lesions. Genes and pathways we discover to be associated with somatic mutation of ARID1A, KRAS and other genes in endometriosis represent novel opportunities for diagnosis and personalized treatment based on the specific landscape of a woman’s disease.