دورية أكاديمية
أعرض في EDS

The coding microsatellite mutation profile of PMS2-deficient colorectal cancer.

التفاصيل البيبلوغرافية
العنوان: The coding microsatellite mutation profile of PMS2-deficient colorectal cancer.
المؤلفون: Bajwa-Ten Broeke SW; Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands; Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: s.w.ten.broeke@umcg.nl., Ballhausen A; Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany., Ahadova A; Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany., Suerink M; Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands., Bohaumilitzky L; Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany., Seidler F; Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany., Morreau H; Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands., van Wezel T; Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands., Krzykalla J; Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany., Benner A; Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany., de Miranda NF; Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands., von Knebel Doeberitz M; Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany., Nielsen M; Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands., Kloor M; Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany.
المصدر: Experimental and molecular pathology [Exp Mol Pathol] 2021 Oct; Vol. 122, pp. 104668. Date of Electronic Publication: 2021 Jul 22.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 0370711 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0945 (Electronic) Linking ISSN: 00144800 NLM ISO Abbreviation: Exp Mol Pathol Subsets: MEDLINE
أسماء مطبوعة: Publication: <2000- > : Amsteram : Elsevier
Original Publication: New York : Academic Press
مواضيع طبية MeSH: Colorectal Neoplasms/*genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/*genetics , DNA Mismatch Repair/*genetics , Mismatch Repair Endonuclease PMS2/*genetics, Aged ; Colorectal Neoplasms/complications ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms, Hereditary Nonpolyposis/complications ; Colorectal Neoplasms, Hereditary Nonpolyposis/pathology ; DNA-Binding Proteins/genetics ; Female ; Germ-Line Mutation/genetics ; Humans ; Male ; Microsatellite Instability ; Microsatellite Repeats/genetics ; Middle Aged ; MutL Protein Homolog 1/genetics ; MutS Homolog 2 Protein/genetics
مستخلص: Lynch syndrome (LS) is caused by a pathogenic heterozygous germline variant in one of the DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. LS-associated colorectal carcinomas (CRCs) are characterized by MMR deficiency and by accumulation of multiple insertions/deletions at coding microsatellites (cMS). MMR deficiency-induced variants at defined cMS loci have a driver function and promote tumorigenesis. Notably, PMS2 variant carriers face only a slightly increased risk of developing CRC. Here, we investigate whether this lower penetrance is also reflected by differences in molecular features and cMS variant patterns. Tumor DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue cores or sections (n = 90). Tumors originated from genetically proven germline pathogenic MMR variant carriers (including 14 PMS2-deficient tumors). The mutational spectrum was analyzed using fluorescently labeled primers specific for 18 cMS previously described as mutational targets in MMR-deficient tumors. Immune cell infiltration was analyzed by immunohistochemical detection of T-cells on FFPE tissue sections. The cMS spectrum of PMS2-deficient CRCs did not show any significant differences from MLH1/MSH2-deficient CRCs. PMS2-deficient tumors, however, displayed lower CD3-positive T-cell infiltration compared to other MMR-deficient cancers (28.00 vs. 55.00 per 0.1 mm 2 , p = 0.0025). Our study demonstrates that the spectrum of potentially immunogenic cMS variants in CRCs from PMS2 gene variant carriers is similar to that observed in CRCs from other MMR gene variant carriers. Lower immune cell infiltration observed in PMS2-deficient CRCs could be the result of alternative mechanisms of immune evasion or immune cell exclusion, similar to those seen in MMR-proficient tumors.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
فهرسة مساهمة: Keywords: HNPCC; Hereditary colorectal cancer; Immunology of cancer; Molecular pathways
المشرفين على المادة: 0 (DNA-Binding Proteins)
0 (G-T mismatch-binding protein)
EC 3.6.1.- (PMS2 protein, human)
EC 3.6.1.3 (MSH2 protein, human)
EC 3.6.1.3 (Mismatch Repair Endonuclease PMS2)
EC 3.6.1.3 (MutL Protein Homolog 1)
EC 3.6.1.3 (MutS Homolog 2 Protein)
تواريخ الأحداث: Date Created: 20210724 Date Completed: 20211222 Latest Revision: 20211222
رمز التحديث: 20240628
DOI: 10.1016/j.yexmp.2021.104668
PMID: 34302852
قاعدة البيانات: MEDLINE
الوصف
تدمد:1096-0945
DOI:10.1016/j.yexmp.2021.104668