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How different KRAS variants impact tumor initiation and progression in vivo has not been thoroughly examined. We hypothesize that the ability of either  KRAS   G12D   or  KRAS   G12V   mutations to initiate tumor formation is context dependent. Amhr2-Cre mice express Cre recombinase in tissues that develop into the fallopian tubes, uterus, and ovaries. We used these mice to conditionally express either the  KRAS   G12V/ +   or KRAS   G12D/ +  mutation. Mice with the genotype  Amhr2-Cre Pten   (fl/fl)    Kras   G12D/ + (G12D mice) had abnormal follicle structures and developed low-grade serous ovarian carcinomas with 100% penetrance within 18 weeks. In contrast, mice with the genotype  Amhr2-Cre Pten   (fl/fl)    Kras   G12V/ +  (G12V mice) had normal follicle structures, and about 90% of them developed uterine tumors with diverse histological features resembling those of leiomyoma and leiomyosarcoma. Granulosa cell tumors also developed in G12V mice. Differences in cell-signaling pathways in the uterine tissues of G12D and G12V mice were identified using RNA sequencing and reverse-phase protein array analyses. We found that CTNNB1, IL1A, IL1B, TNF, TGFB1, APP, and IL6 had the higher activity in G12V mice than in G12D mice. These mouse models will be useful for studying the differences in signaling pathways driven by  Kras   G12V/ +  or  Kras   G12D/ +  mutations to aid development of targeted therapies for specific  KRAS  mutant variants. Our leiomyoma model driven by the  Kras   G12V/ +  mutation will also be useful in deciphering the malignant progression from leiomyoma to leiomyosarcoma.

Differences in gynecologic tumor development in Amhr2-Cre mice with KRASG12D or KRASG12V mutations