Somatic aberrations of mismatch repair genes as a cause of microsatellite‐unstable cancers

<jats:title>Abstract</jats:title><jats:p>Lynch syndrome (<jats:styled-content style="fixed-case">LS</jats:styled-content>) is caused by germline mutations in mismatch repair (<jats:styled-content style="fixed-case">MMR</jats:styled-content>) genes, resulting in microsatellite‐unstable tumours. Approximately 35% of suspected <jats:styled-content style="fixed-case">LS</jats:styled-content> (<jats:styled-content style="fixed-case">sLS</jats:styled-content>) patients test negative for germline <jats:styled-content style="fixed-case">MMR</jats:styled-content> gene mutations, hampering conclusive <jats:styled-content style="fixed-case">LS</jats:styled-content> diagnosis. The aim of this study was to investigate somatic <jats:styled-content style="fixed-case">MMR</jats:styled-content> gene aberrations in microsatellite‐unstable colorectal and endometrial cancers of <jats:styled-content style="fixed-case">sLS</jats:styled-content> patients negative for germline <jats:styled-content style="fixed-case">MMR</jats:styled-content> gene mutations. Suspected <jats:styled-content style="fixed-case">LS</jats:styled-content> cases were selected from a retrospective Clinical Genetics Department diagnostic cohort and from a prospective multicentre population‐based study on <jats:styled-content style="fixed-case">LS</jats:styled-content> in The Netherlands. In total, microsatellite‐unstable tumours of 40 <jats:styled-content style="fixed-case">sLS</jats:styled-content> patients (male/female 20/20, median age 57 years) were screened for somatic <jats:styled-content style="fixed-case">MMR</jats:styled-content> gene mutations by next‐generation sequencing. In addition, loss of heterozygosity (<jats:styled-content style="fixed-case">LOH</jats:styled-content>) of the affected <jats:styled-content style="fixed-case">MMR</jats:styled-content> genes in these tumours as well as in 68 <jats:styled-content style="fixed-case">LS</jats:styled-content>‐associated tumours and 27 microsatellite‐unstable tumours with <jats:italic><jats:styled-content style="fixed-case">MLH1</jats:styled-content></jats:italic> promoter hypermethylation was studied. Of the <jats:styled-content style="fixed-case">sLS</jats:styled-content> cases, 5/40 (13%) tumours had two pathogenic somatic mutations and 16/40 (40%) tumours had a (likely) pathogenic mutation and <jats:styled-content style="fixed-case">LOH</jats:styled-content>. Overall, <jats:styled-content style="fixed-case">LOH</jats:styled-content> of the affected <jats:styled-content style="fixed-case">MMR</jats:styled-content> gene locus was observed in 24/39 (62%) tumours with informative <jats:styled-content style="fixed-case">LOH</jats:styled-content> markers. Of the <jats:styled-content style="fixed-case">LS</jats:styled-content> cases and the tumours with <jats:italic><jats:styled-content style="fixed-case">MLH1</jats:styled-content></jats:italic> promoter hypermethylation, 39/61 (64%) and 2/21 (10%) tumours, respectively, demonstrated <jats:styled-content style="fixed-case">LOH</jats:styled-content>. Half of microsatellite‐unstable tumours of <jats:styled-content style="fixed-case">sLS</jats:styled-content> patients without germline <jats:styled-content style="fixed-case">MMR</jats:styled-content> gene mutations had two (likely) deleterious somatic <jats:styled-content style="fixed-case">MMR</jats:styled-content> gene aberrations, indicating their sporadic origin. Therefore, we advocate adding somatic mutation and <jats:styled-content style="fixed-case">LOH</jats:styled-content> analysis of the <jats:styled-content style="fixed-case">MMR</jats:styled-content> genes to the molecular diagnostic workflow of <jats:styled-content style="fixed-case">LS</jats:styled-content>. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd</jats:p>