Data from Germline and Somatic Fumarate Hydratase Testing in Atypical Uterine Leiomyomata

Abstract

<div>Abstract<p>Women with germline pathogenic variants (PV) in the <i>fumarate hydratase</i> (<i>FH</i>) 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 <i>FH</i> among atypical uterine leiomyomata cases is unknown. To better understand <i>FH</i> 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 <i>FH</i> PV, <i>FH</i> 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 <i>FH</i> PV. There were 48 IHC-defined <i>FH</i>-deficient cases, of which 41 (85%) had <i>FH</i> testing and nine had a germline <i>FH</i> PV, representing 22% of the tested cohort and 18.8% of the <i>FH</i>-deficient cohort. Germline <i>FH</i> 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.</p>Prevention Relevance:<p>Women diagnosed with <i>fumarate hydratase</i> (<i>FH</i>)-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 <i>FH</i>-deficient uterine leiomyomata in the absence of germline <i>FH</i> pathogenic/likely pathogenic variants is needed.</p></div>