Hyeji Jun

Germline and Somatic Fumarate Hydratase Testing in Atypical Uterine Leiomyomata

Abstract Women with germline pathogenic variants (PV) in the fumarate hydratase (FH) gene develop cutaneous and uterine leiomyomata and have an increased risk of developing aggressive renal cell carcinomas. Many of these women are unaware of their cancer predisposition until an atypical uterine leiomyoma is diagnosed during a myomectomy or hysterectomy, making a streamlined genetic counseling process after a pathology-based atypical uterine leiomyoma diagnosis critical. However, the prevalence of germline pathogenic/likely PVs in FH among atypical uterine leiomyomata cases is unknown. To better understand FH germline PV prevalence and current patterns of genetic counseling and germline genetic testing, we undertook a retrospective review of atypical uterine leiomyomata cases at a single large center. We compared clinical characteristics between the FH PV, FH wild-type (WT), and unknown genetic testing cohorts. Of the 144 cases with atypical uterine leiomyomata with evaluable clinical data, only 49 (34%) had documented genetic test results, and 12 (8.3%) had a germline FH PV. There were 48 IHC-defined FH-deficient cases, of which 41 (85%) had FH testing and nine had a germline FH PV, representing 22% of the tested cohort and 18.8% of the FH-deficient cohort. Germline FH PVs were present in 8.3% of evaluable patients, representing 24.5% of the cohort that completed genetic testing. These data highlight the disconnect between pathology and genetic counseling, and help to refine risk estimates that can be used when counseling patients with atypical uterine leiomyomata. Prevention Relevance: Women diagnosed with fumarate hydratase (FH)-deficient uterine leiomyomata are at increased risk of renal cancer. This work suggests a more standardized pathology-genetic counseling referral pathway for these patients, and that research on underlying causes of FH-deficient uterine leiomyomata in the absence of germline FH pathogenic/likely pathogenic variants is needed.

Functional Profiling of p53 and RB Cell Cycle Regulatory Proficiency Suggests Mechanism-Driven Molecular Stratification in Endometrial Carcinoma

Abstract In the United States, Endometrial carcinoma (EC) is the most frequently occurring gynecologic cancer. Many ECs harbor mutations in cell cycle regulatory genes including TP53 and RB1, amongst others. RB and p53 both regulate the G1/S transition while p53 also regulates the G2/M transition and mitotic progression, all of which rely on targetable regulatory kinases. It is likely that many ECs harbor targetable defects in some aspect of cell cycle regulation, but there has been no profiling of p53- or RB- linked cell cycle functional capacity and corresponding therapeutic vulnerabilities in EC cells. Here, we utilize functional and transcriptomic assays on a panel of EC cell lines and patient-derived organoids to characterize the p53 and RB cell cycle regulatory proficiency and linked therapeutic vulnerabilities in EC. We show that TP53 genomic and functional status has poor predictive capacity for EC therapeutic response. Rather, proper RB regulation correlates with response to G1/S targeting CDK4/6 inhibitors, and dysfunction in regulation of mitotic progression correlates with response to Aurora kinase B inhibitors. A subset of TP53 mutant ECs are RB1 wild type, express RB protein, have intact RB regulation, and are sensitive to CDK4/6 inhibitors, suggesting that excluding patients from emerging CDK4/6 inhibitor trials based on aggressive histology or TP53 status should be reconsidered. These findings were validated in vivo in xenograft models. These results can expand current EC molecular stratification to include mechanism-driven subtypes and suggest clinical trials of novel targeted therapies based on biologic understanding for advanced or recurrent EC patients. Significance: We show novel cell cycle regulatory molecular classifications and therapeutic targets for endometrial carcinoma. Intact RB regulation and mitotic progression regulatory defects correlate with CDK4/6 and Aurora kinase B inhibitor sensitivity respectively.