TY - JOUR
T1 - Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents
AU - Olkinuora, Alisa Petriina
AU - Mayordomo, Andrea Constanza
AU - Kauppinen, Anni Katariina
AU - Cerliani, María Belén
AU - Coraglio, Mariana
AU - Collia, Ávila Karina
AU - Gutiérrez, Alejandro
AU - Alvarez, Karin
AU - Cassana, Alessandra
AU - Lopéz-Köstner, Francisco
AU - Jauk, Federico
AU - García-Rivello, Hernán
AU - Ristimäki, Ari
AU - Koskenvuo, Laura
AU - Lepistö, Anna
AU - Nieminen, Taina Tuulikki
AU - Vaccaro, Carlos Alberto
AU - Pavicic, Walter Hernán
AU - Peltomäki, Päivi
N1 - Publisher Copyright:
Copyright © 2022 Olkinuora, Mayordomo, Kauppinen, Cerliani, Coraglio, Collia, Gutiérrez, Alvarez, Cassana, Lopéz-Köstner, Jauk, García-Rivello, Ristimäki, Koskenvuo, Lepistö, Nieminen, Vaccaro, Pavicic and Peltomäki.
PY - 2022/10/28
Y1 - 2022/10/28
N2 - 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.
AB - 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.
KW - DNA glycosylase
KW - exome sequencing
KW - germline variant
KW - MUTYH
KW - NEIL1
KW - NTHL1
KW - OGG1
KW - polyposis
UR - https://www.scopus.com/pages/publications/85141971561
U2 - 10.3389/fonc.2022.870863
DO - 10.3389/fonc.2022.870863
M3 - Article
AN - SCOPUS:85141971561
SN - 2234-943X
VL - 12
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 870863
ER -
