Molecular Classification of Resected Primary Duodenal Adenocarcinoma

Introduction: The molecular and histological characteristics of primary duodenal adenocarcinoma (DA) have been poorly described, which hampers the development of new treatment options. This study aimed to characterize the landscape of chromosomal copy number aberrations (CNAs), microsatellite instability status, and tumor–stroma content, and their association with clinicopathological characteristics of patients with DA. Methods: DNA was extracted from tumor tissues of patients who underwent a primary surgical resection for DA in a single center (2000–2019). Shallow whole genome sequencing (sWGS) was performed to identify chromosomal CNAs and the genomic instability index (GII), for which 25% of the genome was altered, was used to classify tumors as CNAlow or CNAhigh. A PCR-based assay was performed to classify tumors as microsatellite stable (MSS) or instable (MSI). Immunohistochemistry and digital image analysis were performed to determine the tumor–stroma content, for which 50% stroma content was used to classify tumors as stromalow or stromahigh. Results: Among 74 patients with resected DA, sWGS identified 39 (52.7%) CNAlow and 35 (47.3%) CNAhigh tumors. Overall, 16 (21.6%) DAs were MSI. All MSI tumors were CNAlow. The tumor–stroma content was low in 51 (68.9%) and high in 23 (31.1%) of DAs. CNA status was most predictive for 5-year overall survival: 45.5% for patients with CNAlow compared to 31.0% for patients with CNAhigh DA (HR 2.20, 95% CI 1.12–4.30, p = 0.02). Conclusion: About half of resected DAs had CNAlow, which was associated with the most favorable prognosis. Subgrouping of DA could be used for patient stratification in future trials testing novel therapies.