Frontiers in Oncology (Oct 2022)

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

  • Alisa Petriina Olkinuora,
  • Andrea Constanza Mayordomo,
  • Andrea Constanza Mayordomo,
  • Anni Katariina Kauppinen,
  • María Belén Cerliani,
  • Mariana Coraglio,
  • Ávila Karina Collia,
  • Alejandro Gutiérrez,
  • Karin Alvarez,
  • Alessandra Cassana,
  • Francisco Lopéz-Köstner,
  • Federico Jauk,
  • Hernán García-Rivello,
  • Ari Ristimäki,
  • Ari Ristimäki,
  • Laura Koskenvuo,
  • Anna Lepistö,
  • Anna Lepistö,
  • Taina Tuulikki Nieminen,
  • Carlos Alberto Vaccaro,
  • Carlos Alberto Vaccaro,
  • Walter Hernán Pavicic,
  • Walter Hernán Pavicic,
  • Päivi Peltomäki

DOI
https://doi.org/10.3389/fonc.2022.870863
Journal volume & issue
Vol. 12

Abstract

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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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