Pathogenic germline variants among women with uterine cancer by ancestry: A commercial laboratory collaborative research registry study

Abstract

Objective: Uterine cancer (UC) is the most common gynecologic cancer in the United States, and 5-15 % of patients harbor a germline pathogenic variant (gPV) in a cancer predisposition gene. This study aims to characterize the germline landscape of patients with UC by self-identified ancestry.

Methods: Patients with UC who received germline testing were identified from the publicly available Myriad Collaborative Research Registry. Rates of gPVs were calculated, overall and by self-reported ancestry, with a focus on genes associated with UC, including Lynch syndrome (LS) and homologous recombination-related (HR) genes.

Results: Among 35,310 patients with UC, 23,081 (65.4 %) identified as White, 3683 (10.4 %) as Hispanic, 2132 (6.0 %) as Black, 1244 (3.5 %) as Ashkenazi Jewish (AJ), 1093 (3.1 %) as Asian, and 7550 (21.4 %) as Other. Overall, 5141 (14.6 %) patients had a gPV, with highest rates among White (15.5 %) and Asian (17.8 %) compared to Black (10.4 %) and Hispanic (11.6 %) patients, p < 0.0001. LS gPVs were observed in 3155 (8.9 %) patients and was most prevalent in Asian women (12.9 %), particularly MLH1 and MSH2-associated LS. HR-related gPVs were found in 1066 (3.0 %) patients overall and were most common in AJ (4.1 %) and Black (4.0 %) patients, with high rates of BRCA1/2 gPVs in AJ patients and non-BRCA HR-related gPVs in Black patients.

Conclusions: Of the over 35,000 patients with UC, 14.5 % had a gPV identified, supporting consideration of universal germline testing in endometrial cancer given high actionability. We observed heterogeneity in gPVs by self-reported ancestry with Black and Hispanic patients having the lowest rates, potentially contributing to disparities in UC.

Keywords: Germline pathogenic variants; Homologous recombination variants; Lynch syndrome; Self-reported ancestry; Uterine cancer.