Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the colon cancer family registry cohort

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dc.contributor.authorRosty, C.
dc.contributor.authorClendenning, M.
dc.contributor.authorWalsh, M.
dc.contributor.authorEriksen, S.
dc.contributor.authorSouthey, M.
dc.contributor.authorWinship, I.
dc.contributor.authorMacrae, F.
dc.contributor.authorBoussioutas, A.
dc.contributor.authorPoplawski, N.
dc.contributor.authorParry, S.
dc.contributor.authorArnold, J.
dc.contributor.authorYoung, J.
dc.contributor.authorCasey, G.
dc.contributor.authorHaile, R.
dc.contributor.authorGallinger, S.
dc.contributor.authorLe Marchand, L.
dc.contributor.authorNewcomb, P.
dc.contributor.authorPotter, J.
dc.contributor.authorDerycke, M.
dc.contributor.authorLindor, N.
dc.contributor.authoret al.
dc.date.issued2016
dc.description.abstractObjectives: Immunohistochemistry for DNA mismatch repair proteins is used to screen for Lynch syndrome in individuals with colorectal carcinoma (CRC). Although solitary loss of PMS2 expression is indicative of carrying a germline mutation in PMS2, previous studies reported MLH1 mutation in some cases. We determined the prevalence of MLH1 germline mutations in a large cohort of individuals with a CRC demonstrating solitary loss of PMS2 expression. Design: This cohort study included 88 individuals affected with a PMS2-deficient CRC from the Colon Cancer Family Registry Cohort. Germline PMS2 mutation analysis (long-range PCR and multiplex ligation-dependent probe amplification) was followed by MLH1 mutation testing (Sanger sequencing and multiplex ligation-dependent probe amplification). Results: Of the 66 individuals with complete mutation screening, we identified a pathogenic PMS2 mutation in 49 (74%), a pathogenic MLH1 mutation in 8 (12%) and a MLH1 variant of uncertain clinical significance predicted to be damaging by in silico analysis in 3 (4%); 6 (9%) carried variants likely to have no clinical significance. Missense point mutations accounted for most alterations (83%; 9/11) in MLH1. The MLH1 c.113A> G p.Asn38Ser mutation was found in 2 related individuals. One individual who carried the MLH1 intronic mutation c.677+3A>G p.Gln197Argfs*8 leading to the skipping of exon 8, developed 2 tumours, both of which retained MLH1 expression. Conclusions: A substantial proportion of CRCs with solitary loss of PMS2 expression are associated with a deleterious MLH1 germline mutation supporting the screening for MLH1 in individuals with tumours of this immunophenotype, when no PMS2 mutation has been identified.
dc.description.statementofresponsibilityChristophe Rosty, Mark Clendenning, Michael D Walsh, Stine V Eriksen … Nicola Poplawski … Joanne Young … et al.
dc.identifier.citationBMJ Open, 2016; 6(2):e010293-e010293
dc.identifier.doi10.1136/bmjopen-2015-010293
dc.identifier.issn2044-6055
dc.identifier.issn2044-6055
dc.identifier.orcidPoplawski, N. [0000-0002-9372-3325]
dc.identifier.orcidYoung, J. [0000-0002-1514-1522]
dc.identifier.urihttp://hdl.handle.net/2440/116064
dc.language.isoen
dc.publisherBMJ
dc.rightsThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
dc.source.urihttps://doi.org/10.1136/bmjopen-2015-010293
dc.subjectColon Cancer Family Registry Cohort
dc.titleGermline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the colon cancer family registry cohort
dc.typeJournal article
pubs.publication-statusPublished

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