1. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome
- Author
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Maartje Nielsen, Marjolijn J. L. Ligtenberg, Yvonne Tiersma, Juul T. Wijnen, Maran J. W. Olderode-Berends, Encarna Gomez Garcia, B. Redeker, José B. M. Zonneveld, Sanne W. ten Broeke, Frederik J. Hes, Carli M. J. Tops, Peter Devilee, Theo A. M. van Os, Christi J. van Asperen, Hans J. J. P. Gille, Niels de Wind, Heleen M. van der Klift, Arjen R. Mensenkamp, Tom G.W. Letteboer, Yvonne J. Vos, Elsa C. Bik, Mark Drost, S. Verhoef, Liselotte P. van Hest, Anja Wagner, Human Genetics, Human genetics, CCA - Cancer biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, Medical Genetics, and Clinical Genetics
- Subjects
0301 basic medicine ,DNA Mutational Analysis ,pseudogenes ,COLORECTAL-CANCER ,Cohort Studies ,0302 clinical medicine ,Mutation Carrier ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,PMS2 ,Missense mutation ,Genetics (clinical) ,Mismatch Repair Endonuclease PMS2 ,Netherlands ,Medicine(all) ,Genetics ,Brain Neoplasms ,MLH1 ,Neoplastic Syndromes, Hereditary/genetics ,Lynch syndrome ,CMMRD ,missense variants ,immunohistochemistry ,mismatch repair ,030220 oncology & carcinogenesis ,Mutation (genetic algorithm) ,DNA mismatch repair ,Microsatellite Instability ,Colorectal Neoplasms ,EUROPEAN CONSORTIUM CARE ,PSEUDOGENE INTERFERENCE ,congenital, hereditary, and neonatal diseases and abnormalities ,DNA Mutational Analysis/methods ,Biology ,03 medical and health sciences ,Germline mutation ,Neoplastic Syndromes, Hereditary ,Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ,SYNDROME FAMILIES ,CFR PARTICIPANTS ,medicine ,Journal Article ,Humans ,Genetic Predisposition to Disease ,Germ-Line Mutation ,Brain Neoplasms/genetics ,Microsatellite instability ,Genetic Variation ,Mismatch Repair Endonuclease PMS2/genetics ,medicine.disease ,Colorectal Neoplasms/genetics ,Colorectal Neoplasms, Hereditary Nonpolyposis ,GENE ,digestive system diseases ,030104 developmental biology ,PROMOTER HYPERMETHYLATION ,3' DELETIONS ,Cancer research ,NONPOLYPOSIS COLON-CANCER - Abstract
Monoallelic PMS2 germline mutations cause 5-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional MMR deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA and RNA-based strategies are applied to overcome problematic PMS2 mutation analysis due to the presence of pseudogenes and frequent gene conversion events. Here, we determined PMS2 mutation detection yield and mutation spectrum in a nationwide cohort of 396 probands. Furthermore, we studied concordance between tumor IHC/ MSI (immunohistochemistry/ microsatellite-instability) profile and mutation carrier state. Overall, we found 52 different pathogenic PMS2 variants explaining 121 Lynch syndrome and nine CMMRD patients. In vitro MMR assays suggested pathogenicity for three missense variants. Ninety-one PMS2 mutation carriers (70%) showed isolated loss of PMS2 in their tumors, for 31 (24%) no or inconclusive IHC was available, and eight carriers (6%) showed discordant IHC (presence of PMS2 or loss of both MLH1 and PMS2). Ten cases with isolated PMS2 loss (10%; 10/97) harbored MLH1 mutations. We confirmed that recently improved mutation analysis provides a high yield of PMS2 mutations in patients with isolated loss of PMS2 expression. Application of universal tumor pre-screening methods will however miss some PMS2 germline mutation carriers. This article is protected by copyright. All rights reserved.
- Published
- 2016
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