Journal ArticleGermline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate geneSharma, Richa; Oak, Ninad; Chen, Wenan; Gogal, Rose; Kirschner, Martin; Beier, Fabian; Schnieders, Michael J.; Spies, Maria; Nichols, Kim E.; Wlodarski, Marcin<p>Replication Protein A (RPA) is single-strand DNA binding protein that plays a key role in the replication and repair of DNA. RPA is a heterotrimer made of 3 subunits – RPA1, RPA2, and RPA3. Germline pathogenic variants affecting<italic>RPA1</italic>were recently described in patients with Telomere Biology Disorders (TBD), also known as dyskeratosis congenita or short telomere syndrome. Premature telomere shortening is a hallmark of TBD and results in bone marrow failure and predisposition to hematologic malignancies. Building on the finding that somatic mutations in RPA subunit genes occur in ~1% of cancers, we hypothesized that germline RPA alterations might be enriched in human cancers. Because germline<italic>RPA1</italic>mutations are linked to early onset TBD with predisposition to myelodysplastic syndromes, we interrogated pediatric cancer cohorts to define the prevalence and spectrum of rare/novel and putative damaging germline<italic>RPA1</italic>,<italic>RPA2</italic>, and<italic>RPA3</italic>variants. In this study of 5,993 children with cancer, 75 (1.25%) harbored heterozygous rare (non-cancer population allele frequency (AF) &lt; 0.1%) variants in the RPA heterotrimer genes, of which 51 cases (0.85%) had ultra-rare (AF &lt; 0.005%) or novel variants. Compared with Genome Aggregation Database (gnomAD) non-cancer controls, there was significant enrichment of ultra-rare and novel<italic>RPA1</italic>, but not<italic>RPA2</italic>or<italic>RPA3</italic>, germline variants in our cohort (adjusted p-value &lt; 0.05). Taken together, these findings suggest that germline putative damaging variants affecting<italic>RPA1</italic>are found in excess in children with cancer, warranting further investigation into the functional role of these variants in oncogenesis.</p>Frontiers Media S.A.2023-10-0610473929Frontiers in Oncology132234-943Xhttps://doi.org/10.3389/fonc.2023.12295071751688National Science Foundation