title: Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome.
abstract: Mismatch-repair deficient (MMR-D) malignancies include Lynch Syndrome (LS), which is secondary to germline mutations in one of the MMR genes, and the rare childhood-form of constitutional mismatch repair-deficiency (CMMR-D); caused by bi-allelic MMR gene mutations. A hallmark of LS-associated cancers is microsatellite instability (MSI), characterized by coding frameshift mutations (cFSM) in target genes. By contrast, tumors arising in CMMR-D patients are thought to display a somatic mutation pattern differing from LS. This study has the main goal to identify cFSM in MSI target genes relevant in CMMR-D and to compare the spectrum of common somatic mutations, including alterations in DNA polymerases POLE and D1 between LS and CMMR-D. CMMR-D-associated tumors harbored more somatic mutations compared to LS cases, especially in the TP53 gene and in POLE and POLD1, where novel mutations were additionally identified. Strikingly, MSI in classical mononucleotide markers BAT40 and CAT25 was frequent in CMMR-D cases. MSI-target gene analysis revealed mutations in CMMR-D-associated tumors, some of them known to be frequently hit in LS, such as RNaseT2, HT001, and TGFβR2. Our results imply a general role for these cFSM as potential new drivers of MMR-D tumorigenesis.
authors.affiliation: Molecular Oncology and Immunotherapy, Rostock University Medical Center, Rostock, Germany.
authors.forename: Claudia
authors.identifier: 0000-0002-8389-8439
authors.initials: C
authors.lastname: Maletzki
authors.affiliation: Institute of Pathology, Rostock University Medical Center, Rostock, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Huehns
authors.affiliation: Institute of Medical Genetics, Rostock University Medical Center, Rostock, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bauer
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Ripperger
authors.affiliation: Division of Cancer Prevention and Population Sciences, Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston,, Texas.|Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Maureen M
authors.initials: MM
authors.lastname: Mork
authors.affiliation: Division of Cancer Prevention and Population Sciences, Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston,, Texas.|Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Vilar
authors.affiliation: Rostock Cancer Registry, University of Rostock, Rostock, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klöcking
authors.affiliation: Rostock Cancer Registry, University of Rostock, Rostock, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Zettl
authors.affiliation: Institute of Pathology, Rostock University Medical Center, Rostock, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Prall
authors.affiliation: Molecular Oncology and Immunotherapy, Rostock University Medical Center, Rostock, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebacher
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D016368:Frameshift Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D045643:DNA Repair Enzymes
keywords: coding microsatellite mutations; mononucleotide repeats; tumor associated mutations; tumorigenesis