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

Anne M. L. Jansen; Tom van Wezel; Brendy E. W. M. van den Akker; Marina Ventayol Garcia; Dina Ruano; Carli M. J. Tops; Anja Wagner; Tom G. W. Letteboer; Encarna B. Gomez-Garcia; Peter Devilee; Juul T. Wijnen; Frederik J. Hes; Hans Morreau

doi:10.1038/ejhg.2015.252

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

Anne M. L. Jansen, Tom van Wezel, Brendy E. W. M. van den Akker, Marina Ventayol Garcia, Dina Ruano, Carli M. J. Tops, Anja Wagner, Tom G. W. Letteboer, Encarna B. Gomez-Garcia, Peter Devilee, Juul T. Wijnen, Frederik J. Hes, Hans Morreau^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1089-1092
Journal	European Journal of Human Genetics
Volume	24
Issue number	7
DOIs	https://doi.org/10.1038/ejhg.2015.252
Publication status	Published - Jul 2016

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Cite this

Jansen, A. M. L., van Wezel, T., van den Akker, B. E. W. M., Garcia, M. V., Ruano, D., Tops, C. M. J., Wagner, A., Letteboer, T. G. W., Gomez-Garcia, E. B., Devilee, P., Wijnen, J. T., Hes, F. J., & Morreau, H. (2016). Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers. European Journal of Human Genetics, 24(7), 1089-1092. https://doi.org/10.1038/ejhg.2015.252

@article{eb35c2f18bca4633acfaef03eefb6a3d,

title = "Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers",

abstract = "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.",

author = "Jansen, {Anne M. L.} and {van Wezel}, Tom and {van den Akker}, {Brendy E. W. M.} and Garcia, {Marina Ventayol} and Dina Ruano and Tops, {Carli M. J.} and Anja Wagner and Letteboer, {Tom G. W.} and Gomez-Garcia, {Encarna B.} and Peter Devilee and Wijnen, {Juul T.} and Hes, {Frederik J.} and Hans Morreau",

year = "2016",

month = jul,

doi = "10.1038/ejhg.2015.252",

language = "English",

volume = "24",

pages = "1089--1092",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Nature Publishing Group",

number = "7",

}

Jansen, AML, van Wezel, T, van den Akker, BEWM, Garcia, MV, Ruano, D, Tops, CMJ, Wagner, A, Letteboer, TGW, Gomez-Garcia, EB, Devilee, P, Wijnen, JT, Hes, FJ & Morreau, H 2016, 'Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers', European Journal of Human Genetics, vol. 24, no. 7, pp. 1089-1092. https://doi.org/10.1038/ejhg.2015.252

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T1 - Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

AU - Jansen, Anne M. L.

AU - van Wezel, Tom

AU - van den Akker, Brendy E. W. M.

AU - Garcia, Marina Ventayol

AU - Ruano, Dina

AU - Tops, Carli M. J.

AU - Wagner, Anja

AU - Letteboer, Tom G. W.

AU - Gomez-Garcia, Encarna B.

AU - Devilee, Peter

AU - Wijnen, Juul T.

AU - Hes, Frederik J.

AU - Morreau, Hans

PY - 2016/7

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N2 - 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.

AB - 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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