Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

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 leukocyt...

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Autores principales: Jansen, Anne ML, van Wezel, Tom, van den Akker, Brendy EWM, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli MJ, Wagner, Anja, Letteboer, Tom GW, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, Morreau, Hans
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Short Report
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070903/
https://www.ncbi.nlm.nih.gov/pubmed/26648449
http://dx.doi.org/10.1038/ejhg.2015.252
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author Jansen, Anne ML
van Wezel, Tom
van den Akker, Brendy EWM
Ventayol Garcia, Marina
Ruano, Dina
Tops, Carli MJ
Wagner, Anja
Letteboer, Tom GW
Gómez-García, Encarna B
Devilee, Peter
Wijnen, Juul T
Hes, Frederik J
Morreau, Hans
author_facet Jansen, Anne ML
van Wezel, Tom
van den Akker, Brendy EWM
Ventayol Garcia, Marina
Ruano, Dina
Tops, Carli MJ
Wagner, Anja
Letteboer, Tom GW
Gómez-García, Encarna B
Devilee, Peter
Wijnen, Juul T
Hes, Frederik J
Morreau, Hans
author_sort Jansen, Anne ML
collection PubMed
description 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.
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spelling pubmed-50709032016-10-20 Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers Jansen, Anne ML van Wezel, Tom van den Akker, Brendy EWM Ventayol Garcia, Marina Ruano, Dina Tops, Carli MJ Wagner, Anja Letteboer, Tom GW Gómez-García, Encarna B Devilee, Peter Wijnen, Juul T Hes, Frederik J Morreau, Hans Eur J Hum Genet Short Report 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. Nature Publishing Group 2016-07 2015-12-09 /pmc/articles/PMC5070903/ /pubmed/26648449 http://dx.doi.org/10.1038/ejhg.2015.252 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Short Report
Jansen, Anne ML
van Wezel, Tom
van den Akker, Brendy EWM
Ventayol Garcia, Marina
Ruano, Dina
Tops, Carli MJ
Wagner, Anja
Letteboer, Tom GW
Gómez-García, Encarna B
Devilee, Peter
Wijnen, Juul T
Hes, Frederik J
Morreau, Hans
Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers
title Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers
title_full Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers
title_fullStr Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers
title_full_unstemmed Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers
title_short Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers
title_sort combined mismatch repair and pole/pold1 defects explain unresolved suspected lynch syndrome cancers
topic Short Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070903/
https://www.ncbi.nlm.nih.gov/pubmed/26648449
http://dx.doi.org/10.1038/ejhg.2015.252
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