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

Autor:	Olkinuora AP; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland., Mayordomo AC; Programa de Cáncer Hereditario (Pro.Can.He.), Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.; Instituto Multidisciplinario de Biología Celular (IMBICE), Comisión de Investigaciones Científicas de la provincia de Buenos Aires (CICPBA)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de La Plata (UNLP), Buenos Aires, Argentina., Kauppinen AK; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland., Cerliani MB; Instituto Multidisciplinario de Biología Celular (IMBICE), Comisión de Investigaciones Científicas de la provincia de Buenos Aires (CICPBA)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de La Plata (UNLP), Buenos Aires, Argentina., Coraglio M; Unidad de Proctología, Hospital de Gastroenterología 'Dr. Carlos Bonorino Udaondo', Ciudad Autónoma, de Buenos Aires, Argentina., Collia ÁK; Unidad de Proctología, Hospital de Gastroenterología 'Dr. Carlos Bonorino Udaondo', Ciudad Autónoma, de Buenos Aires, Argentina., Gutiérrez A; Unidad de Proctología, Hospital de Gastroenterología 'Dr. Carlos Bonorino Udaondo', Ciudad Autónoma, de Buenos Aires, Argentina., Alvarez K; Centro de cáncer, Clínica Universidad de Los Andes, Santiago, Chile., Cassana A; Unidad de Coloproctología, Clínica Las Condes, Santiago de Chile, Chile., Lopéz-Köstner F; Centro de cáncer, Clínica Universidad de Los Andes, Santiago, Chile., Jauk F; Servicio de Anatomía Patológica, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina., García-Rivello H; Servicio de Anatomía Patológica, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina., Ristimäki A; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.; Department of Pathology, Helsingin ja Uudenmaan Sairaanhoitopiirin Laboratorio (HUSLAB), Helsinki University Hospital and University of Helsinki, Helsinki, Finland., Koskenvuo L; Department of Gastroenterological Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland., Lepistö A; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.; Department of Gastroenterological Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland., Nieminen TT; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland., Vaccaro CA; Programa de Cáncer Hereditario (Pro.Can.He.), Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.; Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB), Hospital Italiano de Buenos Aires (HIBA)-Instituto Universitario Hospital Italiano de Buenos Aires (IUHI)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Argentina., Pavicic WH; Programa de Cáncer Hereditario (Pro.Can.He.), Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.; Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB), Hospital Italiano de Buenos Aires (HIBA)-Instituto Universitario Hospital Italiano de Buenos Aires (IUHI)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires, Argentina., Peltomäki P; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2022 Oct 28; Vol. 12, pp. 870863. Date of Electronic Publication: 2022 Oct 28 (Print Publication: 2022).
DOI:	10.3389/fonc.2022.870863
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Olkinuora, Mayordomo, Kauppinen, Cerliani, Coraglio, Collia, Gutiérrez, Alvarez, Cassana, Lopéz-Köstner, Jauk, García-Rivello, Ristimäki, Koskenvuo, Lepistö, Nieminen, Vaccaro, Pavicic and Peltomäki.)
Databáze:	MEDLINE
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