Background: The incidence and mortality of cancer vary widely across race and ethnicity. This
is attributed to an interplay of socioeconomic factors, environmental exposures, and genetic
background. Cancer genomic studies have underrepresented minorities and individuals of
non-European descent, thus limiting a comprehensive understanding of disparities in the
diagnosis, prognosis, and treatment of cancer among these populations. Furthermore, the social
constructs of race and ethnicity are far from precise categories to understand the biological
underpinnings of such differences. In this study, we use a large real-world data (RWD) patient
cohort to examine associations of genetic ancestry with somatic alterations in known cancer
driver genes.

Methods: We inferred genetic ancestry from approximately 50,000 de-identified records from
cancer patients of diverse histology who underwent tumor genomic profiling with the Tempus xT
next-generation sequencing (NGS) assay. Our cohort includes patients with brain, breast,
colorectal, hematopoietic, lung, and ovarian cancers, among others. We used 654 ancestry
informative markers selected to overlap the target regions of the 648-gene Tempus xT NGS
assay to infer global ancestry proportions at the continental level: Africa (AFR), America (AMR), Europe (EUR), East Asia (EAS), and South Asia (SAS). We imputed race/ethnicity categories
using ancestry proportions on subjects lacking such metadata.

Results: Most patients were of European descent (72%), however, continental genetic ancestry
inference identified 4.7 and 3.8-fold more patients with substantial (>50%) AFR and AMR
ancestry, correspondingly, compared with TCGA. We observed higher percentages of AFR
ancestry patients with prostate, breast, and colorectal cancer (1.8-3.1%) and AMR ancestry
patients with colorectal cancer (2.4%) compared to the overall cohort-level distributions
(p<0.05). Using imputation, we identified 60% and 121% more patients as likely Black and
Hispanic/Latino, respectively. We observed several associations between genetic ancestry with
tumor mutation burden (TMB), e.g., a reduction in median TMB in Asian breast cancer patients
(Asian TMB mean=2.3 m/Mb vs 4.4 for Black, 3.3 for Hispanic, and 4.2 for White; p<0.0001), in
paired tumor/normal sequencing data. Furthermore, we found associations between ancestry
and nonsynonymous somatic mutations in cancer genes, e.g. in CTNNB1 with EAS ancestry
(OR=1.18) and EGFR with EAS (OR=1.24), AMR (OR=1.30), and EUR (OR=0.89) ancestries
(all p<0.001) in lung cancer patients.

Conclusions: Our results support the use of genetic ancestry inference on RWD to improve
upon the social constructs of race and ethnicity, allowing us to better understand the impact of
shared germline genetic or exposure backgrounds into cancer mutational processes that
influence incidence, progression, and outcomes.

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