Documented clinical genetic testing among carriers of hereditary breast and ovarian cancer variants: Ancestry and socioeconomic disparities in the All of Us research program
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Importance
Hereditary breast and ovarian cancer (HBOC) variant carriers benefit from risk-reducing interventions, but only if identified. The extent to which carriers are clinically recognized, and whether recognition is equitable across diverse populations, is poorly characterized in a single large U.S. cohort.
Objective
To estimate P/LP HBOC carrier prevalence across genetic ancestry groups, quantify documented clinical genetic testing among carriers, and evaluate ancestry and socioeconomic disparities in testing.
Design, Setting, and Participants
Cross-sectional analysis of the All of Us Research Program Controlled Tier (Curated Data Repository v8/C2024Q3R9), comprising participants with short-read whole-genome sequencing and linked electronic health record (EHR) and survey data. Carriers were ascertained from research genomic data independent of clinical testing.
Exposures
Genetically inferred ancestry (African [AFR], Admixed American [AMR], East Asian [EAS], European [EUR], Middle Eastern [MID], South Asian [SAS]); self-reported household income and educational attainment.
Main Outcomes and Measures
(1) Carrier prevalence with Wilson 95% CIs; (2) documented clinical genetic testing (procedure codes) among carriers; (3) adjusted odds of documented testing among women, by ancestry, before and after socioeconomic adjustment, using multivariable logistic regression.
Results
Among 414,830 participants, P/LP HBOC carrier prevalence was 1.42% (95% CI, 1.38–1.45) overall and similar across ancestry groups (AFR 1.24%, AMR 1.32%, EAS 1.19%, EUR 1.52%, MID 1.68%, SAS 1.33%; overlapping CIs). Among 250,071 women in the testing analysis, documented clinical genetic testing was rare: only 74 of 5,878 carriers overall (1.3%) and 59 of 3,572 European-ancestry carriers (1.7%) had a documented test, with counts below reportable thresholds in all other ancestry groups. African-ancestry women had lower adjusted odds of documented testing than European-ancestry women (Model 1 adjusted odds ratio [aOR], 0.32; 95% CI, 0.27–0.39), an association that attenuated but persisted after adjustment for income and education (Model 2 aOR, 0.48; 95% CI, 0.40–0.58; P < 0.001); Admixed American women also had reduced adjusted odds (aOR, 0.71; 95% CI, 0.61–0.84). Lower income and lower education were independently and dose-dependently associated with lower testing odds (income <$25,000 aOR, 0.46; high-school education aOR, 0.54).
Conclusions and Relevance
High-risk HBOC variant carriers are present across all ancestry groups at similar frequencies, yet documented clinical genetic testing was disparate in the different ancestry groups. African-ancestry women experience a testing gap that is not fully explained by socioeconomic position, implicating structural barriers in access and referral. Population-level strategies that decouple carrier identification from current referral pathways may be required to close this gap.
Key Points
Question
Among carriers of pathogenic or likely-pathogenic hereditary breast and ovarian cancer (HBOC) variants identified from research whole-genome sequencing, how often is clinical genetic testing documented, and does it differ by genetic ancestry and socioeconomic position?
Findings
In this cross-sectional study of 414,830 All of Us participants with whole-genome sequencing, P/LP HBOC carrier prevalence was similar across genetic ancestry groups (∼1.4%), yet documented clinical genetic testing among carriers was rare (1.3% overall; 1.7% among European-ancestry carriers; suppressed in other groups). African-ancestry women had markedly lower adjusted odds of documented testing, a gap that persisted after adjustment for income and education.
Meaning
High-risk variant carriers are distributed across all ancestry groups, but the overwhelming majority are never clinically identified, and African-ancestry women face an access gap not explained by socioeconomic position alone.
