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Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents

Recently, biallelic germline variants of the DNA glycosylase genes MUTYH and NTHL1 were linked to polyposis susceptibility. Significant fractions remain without a molecular explanation, warranting searches for underlying causes. We used exome sequencing to investigate clinically well-defined adenoma...

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Autores principales: Olkinuora, Alisa Petriina, Mayordomo, Andrea Constanza, Kauppinen, Anni Katariina, Cerliani, María Belén, Coraglio, Mariana, Collia, Ávila Karina, Gutiérrez, Alejandro, Alvarez, Karin, Cassana, Alessandra, Lopéz-Köstner, Francisco, Jauk, Federico, García-Rivello, Hernán, Ristimäki, Ari, Koskenvuo, Laura, Lepistö, Anna, Nieminen, Taina Tuulikki, Vaccaro, Carlos Alberto, Pavicic, Walter Hernán, Peltomäki, Päivi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9650540/
https://www.ncbi.nlm.nih.gov/pubmed/36387175
http://dx.doi.org/10.3389/fonc.2022.870863
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author Olkinuora, Alisa Petriina
Mayordomo, Andrea Constanza
Kauppinen, Anni Katariina
Cerliani, María Belén
Coraglio, Mariana
Collia, Ávila Karina
Gutiérrez, Alejandro
Alvarez, Karin
Cassana, Alessandra
Lopéz-Köstner, Francisco
Jauk, Federico
García-Rivello, Hernán
Ristimäki, Ari
Koskenvuo, Laura
Lepistö, Anna
Nieminen, Taina Tuulikki
Vaccaro, Carlos Alberto
Pavicic, Walter Hernán
Peltomäki, Päivi
author_facet Olkinuora, Alisa Petriina
Mayordomo, Andrea Constanza
Kauppinen, Anni Katariina
Cerliani, María Belén
Coraglio, Mariana
Collia, Ávila Karina
Gutiérrez, Alejandro
Alvarez, Karin
Cassana, Alessandra
Lopéz-Köstner, Francisco
Jauk, Federico
García-Rivello, Hernán
Ristimäki, Ari
Koskenvuo, Laura
Lepistö, Anna
Nieminen, Taina Tuulikki
Vaccaro, Carlos Alberto
Pavicic, Walter Hernán
Peltomäki, Päivi
author_sort Olkinuora, Alisa Petriina
collection PubMed
description Recently, biallelic germline variants of the DNA glycosylase genes MUTYH and NTHL1 were linked to polyposis susceptibility. Significant fractions remain without a molecular explanation, warranting searches for underlying causes. We used exome sequencing to investigate clinically well-defined adenomatous polyposis cases and families from Finland (N=34), Chile (N=21), and Argentina (N=12), all with known susceptibility genes excluded. Nine index cases (13%) revealed germline variants with proven or possible pathogenicity in the DNA glycosylase genes, involving NEIL1 (mono- or biallelic) in 3 cases, MUTYH (monoallelic) in 3 cases, NTHL1 (biallelic) in 1 case, and OGG1 (monoallelic) in 2 cases. NTHL1 was affected with the well-established, pathogenic c.268C>T, p.(Gln90Ter) variant. A recurrent heterozygous NEIL1 c.506G>A, p.(Gly169Asp) variant was observed in two families. In a Finnish family, the variant occurred in trans with a truncating NEIL1 variant (c.821delT). In an Argentine family, the variant co-occurred with a genomic deletion of exons 2 – 11 of PMS2. Mutational signatures in tumor tissues complied with biological functions reported for NEIL1. Our results suggest that germline variants in DNA glycosylase genes may occur in a non-negligible proportion of unexplained colon polyposis cases and may predispose to tumor development.
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spelling pubmed-96505402022-11-15 Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents Olkinuora, Alisa Petriina Mayordomo, Andrea Constanza Kauppinen, Anni Katariina Cerliani, María Belén Coraglio, Mariana Collia, Ávila Karina Gutiérrez, Alejandro Alvarez, Karin Cassana, Alessandra Lopéz-Köstner, Francisco Jauk, Federico García-Rivello, Hernán Ristimäki, Ari Koskenvuo, Laura Lepistö, Anna Nieminen, Taina Tuulikki Vaccaro, Carlos Alberto Pavicic, Walter Hernán Peltomäki, Päivi Front Oncol Oncology Recently, biallelic germline variants of the DNA glycosylase genes MUTYH and NTHL1 were linked to polyposis susceptibility. Significant fractions remain without a molecular explanation, warranting searches for underlying causes. We used exome sequencing to investigate clinically well-defined adenomatous polyposis cases and families from Finland (N=34), Chile (N=21), and Argentina (N=12), all with known susceptibility genes excluded. Nine index cases (13%) revealed germline variants with proven or possible pathogenicity in the DNA glycosylase genes, involving NEIL1 (mono- or biallelic) in 3 cases, MUTYH (monoallelic) in 3 cases, NTHL1 (biallelic) in 1 case, and OGG1 (monoallelic) in 2 cases. NTHL1 was affected with the well-established, pathogenic c.268C>T, p.(Gln90Ter) variant. A recurrent heterozygous NEIL1 c.506G>A, p.(Gly169Asp) variant was observed in two families. In a Finnish family, the variant occurred in trans with a truncating NEIL1 variant (c.821delT). In an Argentine family, the variant co-occurred with a genomic deletion of exons 2 – 11 of PMS2. Mutational signatures in tumor tissues complied with biological functions reported for NEIL1. Our results suggest that germline variants in DNA glycosylase genes may occur in a non-negligible proportion of unexplained colon polyposis cases and may predispose to tumor development. Frontiers Media S.A. 2022-10-28 /pmc/articles/PMC9650540/ /pubmed/36387175 http://dx.doi.org/10.3389/fonc.2022.870863 Text en Copyright © 2022 Olkinuora, Mayordomo, Kauppinen, Cerliani, Coraglio, Collia, Gutiérrez, Alvarez, Cassana, Lopéz-Köstner, Jauk, García-Rivello, Ristimäki, Koskenvuo, Lepistö, Nieminen, Vaccaro, Pavicic and Peltomäki 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
Olkinuora, Alisa Petriina
Mayordomo, Andrea Constanza
Kauppinen, Anni Katariina
Cerliani, María Belén
Coraglio, Mariana
Collia, Ávila Karina
Gutiérrez, Alejandro
Alvarez, Karin
Cassana, Alessandra
Lopéz-Köstner, Francisco
Jauk, Federico
García-Rivello, Hernán
Ristimäki, Ari
Koskenvuo, Laura
Lepistö, Anna
Nieminen, Taina Tuulikki
Vaccaro, Carlos Alberto
Pavicic, Walter Hernán
Peltomäki, Päivi
Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents
title Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents
title_full Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents
title_fullStr Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents
title_full_unstemmed Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents
title_short Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents
title_sort mono- and biallelic germline variants of dna glycosylase genes in colon adenomatous polyposis families from two continents
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9650540/
https://www.ncbi.nlm.nih.gov/pubmed/36387175
http://dx.doi.org/10.3389/fonc.2022.870863
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