Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene

Richa Sharma; Ninad Oak; Wenan Chen; Rose Gogal; Martin Kirschner; Fabian Beier; Michael J. Schnieders; Maria Spies; Kim E. Nichols; Marcin Wlodarski

doi:10.3389/fonc.2023.1229507

Back

Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene

Journal article

Open access

Peer reviewed

Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene

Richa Sharma, Ninad Oak, Wenan Chen, Rose Gogal, Martin Kirschner, Fabian Beier, Michael J. Schnieders, Maria Spies, Kim E. Nichols and Marcin Wlodarski

Frontiers in oncology, Vol.13, 1229507

10/06/2023

DOI: 10.3389/fonc.2023.1229507

PMCID: PMC10588448

PMID: 37869077

Files and links (1)

url

https://doi.org/10.3389/fonc.2023.1229507View

Published (Version of record) Open Access

Abstract

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 RPA1 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 RPA1 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 RPA1 , RPA2 , and RPA3 variants. In this study of 5,993 children with cancer, 75 (1.25%) harbored heterozygous rare (non-cancer population allele frequency (AF) < 0.1%) variants in the RPA heterotrimer genes, of which 51 cases (0.85%) had ultra-rare (AF < 0.005%) or novel variants. Compared with Genome Aggregation Database (gnomAD) non-cancer controls, there was significant enrichment of ultra-rare and novel RPA1 , but not RPA2 or RPA3 , germline variants in our cohort (adjusted p-value < 0.05). Taken together, these findings suggest that germline putative damaging variants affecting RPA1 are found in excess in children with cancer, warranting further investigation into the functional role of these variants in oncogenesis.

Details

Title: Subtitle: Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene
Creators: Richa Sharma - St. Jude Children's Research Hospital
Ninad Oak - St. Jude Children's Research Hospital
Wenan Chen - St. Jude Children's Research Hospital
Rose Gogal - University of Iowa
Martin Kirschner - RWTH Aachen University
Fabian Beier - RWTH Aachen University
Michael J. Schnieders - University of Iowa
Maria Spies - University of Iowa
Kim E. Nichols - St. Jude Children's Research Hospital
Marcin Wlodarski - St. Jude Children's Research Hospital
Resource Type: Journal article
Publication Details: Frontiers in oncology, Vol.13, 1229507
DOI: 10.3389/fonc.2023.1229507
PMID: 37869077
PMCID: PMC10588448
NLM abbreviation: Front Oncol
ISSN: 2234-943X
eISSN: 2234-943X
Language: English
Date published: 10/06/2023
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiation Oncology; Biochemistry and Molecular Biology; Chemical and Biochemical Engineering
Record Identifier: 9984476429102771

Metrics

5 Record Views

4 Times Cited - Web of Science