Overall cancer risk in people with deleterious germline DDX41 variants

Abstract

Germline loss of function (LoF) DDX41 variants predispose to late-onset hematopoietic malignancies (HMs), predominantly of myeloid lineage. Among 43 families with germline DDX41 LoF variants, bone marrow (BM) biopsies in those without (n=8) or with malignancies (n=21) revealed mild dysplasia in peripheral blood (57%) and BM (88%), long before the average age of DDX41-related HM onset. Therefore, we recommend baseline bone marrow biopsies in people with germline DDX41LoF alleles to avoid over-diagnosis of myelodysplastic syndromes. A variety of solid tumors were also observed in our cohort, with 24% penetrance by age 75. Although acquired DDX41 mutations are common in HMs, we failed to identify such alleles in solid tumors arising in those with germline DDX41LoF variants (n=15), suggesting an alternative mechanism driving solid tumor development. Furthermore, 33% of pedigrees in which >15% of first-degree relatives including the proband were diagnosed with a solid tumor had second germline deleterious variants in other cancerpredisposition genes, likely serving as primary cancer drivers. Finally, both lymphoblastoid cell lines and primary peripheral blood from individuals with germline DDX41LoF variants exhibited differential levels of inflammation-associated proteins. These data provide evidence of inflammatory dysfunction mediated by germline DDX41LoF alleles that may contribute to solid tumor growth in the context of additional germline cancer-associated variants. For those with HMs and personal/family histories of solid tumors, we recommend broad germline testing. DDX41 may be an indirect modifier of solid tumor pathogenesis compared to its tumor suppressor function within hematopoietic tissues, a hypothesis that can be addressed in future work.