Germline variants across self-reported racial populations with urothelial carcinoma (UC).

Abstract

4569 Background: Prior studies of the UC germline landscape centered around White patients with minimal representation of other racial populations. Herein, we examine the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 2,582 patients with UC from various racial populations. Methods: 2,582 patients with UC underwent germline testing of 1 to 126 genes using massively parallel sequencing with customized capture bait-sets to analyze exonic regions, flanking intronic regions, and copy number alterations (CNAs). P/LP variants including single nucleotide variants, indels and CNAs were reported. Fisher’s Exact test and multivariable logistic regression were used after accounting for the number of genes tested, age at diagnosis, site of disease (upper versus lower tract), gender, family history of UC, and personal history of any cancer. Results: Among the 2,582 patients with UC, median age at diagnosis was 63 years (range, 4-90) and 1158 (44.8%) were female. There were 58 Asians (2.2%), 110 Blacks (4.3%), and 2,414 Whites (93.5%). Overall, 1,639/2,582 (63.5%) patients had a personal history of another cancer and 284/2,393 (11.9%) had history of UC in a family member. 465 P/LP variants were identified in 18% of patients, among whom 286 (11.1%) harbored ≥1 clinically actionable variants. P/LP in cancer-associated genes were most frequently reported in MSH2 (72/2,512, 2.9%), monoallelic MUTYH (45/2,136, 2.1%), BRCA2 (44/2,299, 1.9%) and MSH6 (47/2,511, 1.9%). Patients with upper tract UC had significantly more P/LP (72/247, 29.1%) compared to lower tract UC (332/2,076, 16%, p= 1.3x10-5). Age at diagnosis, gender, personal history of other primary cancers, or family history of UC were not significantly associated with the prevalence of P/LP variants. There were no significant differences ( p= 0.33) in P/LP variants across Asians (11/58, 19.0%), Blacks (14/110, 12.7%), and Whites (440/2,414, 18.2%) although a trend towards lower P/LP in Blacks is notable. Compared to Whites, Blacks and Asians harbored significantly more variants of unknown significance (VUS, Whites vs Blacks: 241/2414 vs 25/110, p= 0.0015; Whites vs Asians: 241/2414 vs 17/58, p= 4e-7). Asians with UC harbored significantly more P/LP variants in ATM (2/50, 4%) compared to Whites (30/2122, 1.4%, OR = 1.1 [95% CI, 1.0-1.2]) and Asian controls from the gnomAD Database. There were no significant differences across racial populations for other highly altered genes ( BRCA1/2, CHEK2, FH, MSH2/6, MUTYH) or for actionable variants. Conclusions: Germline P/LP variants were identified in 18% of patients with UC and were enriched in upper tract tumors. Although no significant differences in P/LP prevalence were noted among patients of different racial populations, a trend towards lower P/LP in Blacks and a higher rate of VUS in Asians and Blacks suggest that ongoing analysis by genetic ancestry may provide richer admixture data and insights.