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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.

SUBMITTER: Jansen AM 

PROVIDER: S-EPMC5070903 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other

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

Jansen Anne Ml AM   van Wezel Tom T   van den Akker Brendy Ewm BE   Ventayol Garcia Marina M   Ruano Dina D   Tops Carli Mj CM   Wagner Anja A   Letteboer Tom Gw TG   Gómez-García Encarna B EB   Devilee Peter P   Wijnen Juul T JT   Hes Frederik J FJ   Morreau Hans H  

European journal of human genetics : EJHG 20151209 7

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. N  ...[more]

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