Abstract 5164: Deleterious germline <i>DDX41</i> variants drive solid tumors in conjunction with second cancer risk alleles and a pro-inflammatory environment

Abstract The presence of solid tumors in those with deleterious germline DDX41 variants in addition to the expected myeloid malignancies suggests that these alleles could contribute to solid tumor development. To test if DDX41 cancer risk alleles contribute directly to solid tumor development, we analyzed somatic mutations in solid tumors from people with these variants. We did not detect any somatic DDX41 mutations (n=18) in contrast to myeloid malignancies in which somatic DDX41 mutations are common. Moreover, we observed that among families with hematopoietic malignancies and solid tumors, 30% had second germline deleterious variants in other cancer-associated genes. Together, these data suggest that DDX41 may contribute to solid tumor development indirectly. Since DDX41 regulates innate immunity, we hypothesized that DDX41 cancer risk alleles could contribute to solid tumor development via inflammation. We measured inflammatory cytokine levels in conditioned media from lymphoblastoid cell lines with deleterious germline DDX41 variants (DDX41var/+) and found elevated levels of some cytokines in DDX41var/+ versus controls. Western blots confirmed elevated NF-kB p65 subunit levels and increased nuclear NF-kB localization (p=0.008), suggesting that the DDX41-related inflammatory milieu may be partially characterized by dysregulated NF-kB-driven cytokine expression. To investigate the possibility that DDX41 variants drive an inflammatory milieu, we performed flow cytometry on peripheral blood of germline Ddx41+/- versus WT mice. We found a 20% increase in T-cells (p=0.0069) in the context of Ddx41-deficiency, suggesting that Ddx41-deficiency contributes to inflammation in this mouse model. To test our hypothesis that DDX41 is a modifier of solid tumor pathogenesis, we have bred Ddx41+/- mice to ApcMin/+ mice, which develop intestinal adenomas and are a model of human colon cancer. At three months of age, our preliminary data suggest there are more adenomas in Ddx41-deficient versus WT mice. We are now testing whether Ddx41-deficiency in the hematopoietic compartment drives the elevated adenoma levels, allowing us to delineate the role of immune cells in solid tumor development in the context of Ddx41-deficiency. Overall, our findings suggest germline deleterious DDX41 variants contribute indirectly to solid tumor development in the context of other germline cancer risk disorders, possibly through elevated inflammation. Citation Format: Sophia C. Korotev, Joshua Y. Strauss, Salina Dominguez, Ashwin Koppayi, Hina Usman, Kehan Ren, Honghao Bi, Peng Ji, Lucy Godley. Deleterious germline DDX41 variants drive solid tumors in conjunction with second cancer risk alleles and a pro-inflammatory environment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5164.