Molecular Basis of Mismatch Repair Protein Deficiency in Tumors from Lynch Suspected Cases with Negative Germline Test Results

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http://hdl.handle.net/10138/319290

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Olkinuora , A , Gylling , A , Almusa , H , Eldfors , S , Lepistö , A , Mecklin , J-P , Nieminen , T T & Peltomäki , P 2020 , ' Molecular Basis of Mismatch Repair Protein Deficiency in Tumors from Lynch Suspected Cases with Negative Germline Test Results ' , Cancers , vol. 12 , no. 7 , 1853 . https://doi.org/10.3390/cancers12071853

Title: Molecular Basis of Mismatch Repair Protein Deficiency in Tumors from Lynch Suspected Cases with Negative Germline Test Results
Author: Olkinuora, Alisa; Gylling, Annette; Almusa, Henrikki; Eldfors, Samuli; Lepistö, Anna; Mecklin, Jukka-Pekka; Nieminen, Taina Tuulikki; Peltomäki, Päivi
Contributor: University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, HUS Abdominal Center
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Department of Medical and Clinical Genetics
Date: 2020-07
Language: eng
Number of pages: 15
Belongs to series: Cancers
ISSN: 2072-6694
URI: http://hdl.handle.net/10138/319290
Abstract: Some 10-50% of Lynch-suspected cases with abnormal immunohistochemical (IHC) staining remain without any identifiable germline mutation of DNA mismatch repair (MMR) genes. MMR proteins form heterodimeric complexes, giving rise to distinct IHC patterns when mutant. Potential reasons for not finding a germline mutation include involvement of an MMR gene not predicted by the IHC pattern, epigenetic mechanism of predisposition, primary mutation in another DNA repair or replication-associated gene, and double somatic MMR gene mutations. We addressed these possibilities by germline and tumor studies in 60 Lynch-suspected cases ascertained through diagnostics (n= 55) or research (n= 5). All cases had abnormal MMR protein staining in tumors but no point mutation or large rearrangement of the suspected MMR genes in the germline. In diagnostic practice, MSH2/MSH6 (MutS Homolog 2/MutS Homolog 6) deficiency promptsMSH2mutation screening; in our study, 3/11 index individuals (27%) with this IHC pattern revealed pathogenic germline mutations inMSH6. Individuals with isolated absence of MSH6 are routinely screened forMSH6mutations alone; we found a predisposing mutation inMSH2in 1/7 such cases (14%). Somatic deletion of theMSH2-MSH6region, joint loss of MSH6 and MSH3 (MutS Homolog 3) proteins, and hindered MSH2/MSH6 dimerization offered explanations to misleading IHC patterns. Constitutional epimutation hypothesis was pursued in the MSH2 and/or MSH6-deficient cases plus 38 cases with MLH1 (MutL Homolog 1)-deficient tumors; a primaryMLH1epimutation was identified in one case with an MLH1-deficient tumor. We conclude that bothMSH2andMSH6should be screened in MSH2/6- and MSH6-deficient cases. In MLH1-deficient cases, constitutional epimutations ofMLH1warrant consideration.
Subject: Lynch syndrome
DNA mismatch repair
colorectal cancer
deep sequencing
NONPOLYPOSIS COLORECTAL-CANCER
FREQUENT CAUSE
MUTATIONS
MLH1
MSH2
METHYLATION
MANAGEMENT
CARCINOMA
DIAGNOSIS
DEFECTS
3122 Cancers
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