Comprehensive Analysis of Genomic Variations in Pancreatic Adenocarcinoma by Race

Racial disparities in pancreatic ductal adenocarcinoma (PDAC) incidence and outcomes persist even after adjusting for access to care and treatment received, suggesting a role for tumor-specific molecular factors. This study aimed to compare the mutational landscape of PDAC tumor samples across racial groups using a large, diverse patient cohort.

Genetic variations were analyzed using data from the AACR Project GENIE registry. Adult patients with PDAC treated at Memorial Sloan Kettering Cancer Center or Dana-Farber Cancer Institute who underwent next-generation sequencing were included. Somatic mutations in 680 genes were compared among White, Black, and Asian patients, controlling for multiple comparisons.

Among 4327 patients (mean age 66.4 years, 53% male), 61% had localized disease, while 39% had metastatic disease. The most commonly mutated genes were KRAS, TP53, SMAD4, ARID1A, KMT2D, RNF43, CDKN2A, and COL7A1. The median number of mutations per patient was 4, irrespective of race (p-value = 0.45). Asian patients had significantly fewer CDKN2A mutations than White patients (0.7% vs. 9.1%, p = 1.9 × 10^-5) and Black patients (0.7% vs. 8.1%, p = 7.4 × 10^-4) as well as fewer cell-cycle-related mutations (4.4% vs. 11.5% and 13.0%, respectively; p = 0.012). No significant racial differences were observed in tumor mutational burden (TMB), microsatellite instability, or clinically targetable mutations (p-values > 0.05).

Asian patients with PDAC had fewer CDKN2A mutations, a genotype linked to improved survival and reduced tumor aggressiveness. Genomic profiles were otherwise similar across races, suggesting that disparities are likely driven by non-genomic factors beyond DNA sequence alterations, such as epigenetic modifications or posttranslational changes. Integrating multiomic and clinical data is crucial to better understand and address these disparities.