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Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome
Mariano Golubicki, … , Marina Antelo, Sergi Castellví-Bel
Mariano Golubicki, … , Marina Antelo, Sergi Castellví-Bel
Published August 25, 2020
Citation Information: JCI Insight. 2020;5(18):e140698. https://doi.org/10.1172/jci.insight.140698.
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Research Article Gastroenterology Genetics

Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome

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Abstract

Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a male patient with LLS with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR/Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability, and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance.

Authors

Mariano Golubicki, Laia Bonjoch, José G. Acuña-Ochoa, Marcos Díaz-Gay, Jenifer Muñoz, Miriam Cuatrecasas, Teresa Ocaña, Soledad Iseas, Guillermo Mendez, Daniel Cisterna, Stephanie A. Schubert, Maartje Nielsen, Tom van Wezel, Yael Goldberg, Eli Pikarsky, Juan Robbio, Enrique Roca, Antoni Castells, Francesc Balaguer, Marina Antelo, Sergi Castellví-Bel

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Figure 6

MCM8 genetic variants displayed less ability to repair damaged DNA.

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MCM8 genetic variants displayed less ability to repair damaged DNA.
(A)...
(A) Overview of the DNA repair experiment (comet assay). (B) Representative images of neutral comet assay (n = 3). Upper panel, DNA damage impairment detected in MCM8KO cells in comparison with MCM8WTcells. Lower panel, MCM8KO 5.2 expressing p.(Ile138Met) or p.(Lys118Glufs*5) (short format is displayed). MCM8 proteins showed lower DNA repair capacity than the rescued phenotype (MCM8WT). Scale bar: 100 μm. (C) Quantitative analysis of DNA damage in the 3 independent experiments, measured as the amount of tail DNA. Box-and-whisker plots represent 25th to 75th and 5th to 95th percentiles, respectively. The solid line represents the median value. **P < 0.01, ***P < 0.001, 1-way ANOVA with Tukey’s post hoc test.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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