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

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 Disorder...

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Autores principales: Sharma, Richa, Oak, Ninad, Chen, Wenan, Gogal, Rose, Kirschner, Martin, Beier, Fabian, Schnieders, Michael J., Spies, Maria, Nichols, Kim E., Wlodarski, Marcin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10588448/
https://www.ncbi.nlm.nih.gov/pubmed/37869077
http://dx.doi.org/10.3389/fonc.2023.1229507
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author Sharma, Richa
Oak, Ninad
Chen, Wenan
Gogal, Rose
Kirschner, Martin
Beier, Fabian
Schnieders, Michael J.
Spies, Maria
Nichols, Kim E.
Wlodarski, Marcin
author_facet Sharma, Richa
Oak, Ninad
Chen, Wenan
Gogal, Rose
Kirschner, Martin
Beier, Fabian
Schnieders, Michael J.
Spies, Maria
Nichols, Kim E.
Wlodarski, Marcin
author_sort Sharma, Richa
collection PubMed
description 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.
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spelling pubmed-105884482023-10-21 Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene Sharma, Richa Oak, Ninad Chen, Wenan Gogal, Rose Kirschner, Martin Beier, Fabian Schnieders, Michael J. Spies, Maria Nichols, Kim E. Wlodarski, Marcin Front Oncol Oncology 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. Frontiers Media S.A. 2023-10-06 /pmc/articles/PMC10588448/ /pubmed/37869077 http://dx.doi.org/10.3389/fonc.2023.1229507 Text en Copyright © 2023 Sharma, Oak, Chen, Gogal, Kirschner, Beier, Schnieders, Spies, Nichols and Wlodarski https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Sharma, Richa
Oak, Ninad
Chen, Wenan
Gogal, Rose
Kirschner, Martin
Beier, Fabian
Schnieders, Michael J.
Spies, Maria
Nichols, Kim E.
Wlodarski, Marcin
Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene
title Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene
title_full Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene
title_fullStr Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene
title_full_unstemmed Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene
title_short Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene
title_sort germline landscape of rpa1, rpa2 and rpa3 variants in pediatric malignancies: identification of rpa1 as a novel cancer predisposition candidate gene
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10588448/
https://www.ncbi.nlm.nih.gov/pubmed/37869077
http://dx.doi.org/10.3389/fonc.2023.1229507
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