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 journalArticleAcademicpeer-review

81 Citations (Web of Science)


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 languageEnglish
Pages (from-to)1089-1092
JournalEuropean Journal of Human Genetics
Issue number7
Publication statusPublished - Jul 2016

Cite this