title: Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers.
abstract: Many suspected Lynch Syndrome (sLS) patients who lack mismatch repair (MMR) germline gene variants and MLH1 or MSH2 hypermethylation are currently explained by somatic MMR gene variants or, occasionally, by germline POLE variants. To further investigate unexplained sLS patients, we analyzed leukocyte and tumor DNA of 62 sLS patients using gene panel sequencing including the POLE, POLD1 and MMR genes. Forty tumors showed either one, two or more somatic MMR variants predicted to affect function. Nine sLS tumors showed a likely ultramutated phenotype and were found to carry germline (n=2) or somatic variants (n=7) in the POLE/POLD1 exonuclease domain (EDM). Six of these POLE/POLD1-EDM mutated tumors also carried somatic MMR variants. Our findings suggest that faulty proofreading may result in loss of MMR and thereby in microsatellite instability.
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Anne Ml
authors.initials: AM
authors.lastname: Jansen
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Tom
authors.identifier: 0000-0001-5773-7730
authors.initials: T
authors.lastname: van Wezel
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Brendy Ewm
authors.initials: BE
authors.lastname: van den Akker
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Marina
authors.initials: M
authors.lastname: Ventayol Garcia
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Dina
authors.initials: D
authors.lastname: Ruano
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Carli Mj
authors.initials: CM
authors.lastname: Tops
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Anja
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Tom Gw
authors.initials: TG
authors.lastname: Letteboer
authors.affiliation: Department of Clinical Genetics, University Hospital Maastricht, Maastricht, The Netherlands.
authors.forename: Encarna B
authors.initials: EB
authors.lastname: Gómez-García
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.|Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Juul T
authors.initials: JT
authors.lastname: Wijnen
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Frederik J
authors.identifier: 0000-0002-3025-0882
authors.initials: FJ
authors.lastname: Hes
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
mesh_terms: D000328:Adult; D000368:Aged; D020134:Catalytic Domain; D060965:Clonal Evolution; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair; D004257:DNA Polymerase II / Q000737:chemistry / Q000235:genetics*; D004258:DNA Polymerase III / Q000737:chemistry / Q000235:genetics*; D005260:Female; D042822:Genomic Instability; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1 / Q000235:genetics; D051718:MutS Homolog 2 Protein / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins
chemical_list: C501486:MLH1 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; C434055:POLD1 protein, human; D004257:DNA Polymerase II; D004258:DNA Polymerase III; C119525:POLE protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein