Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/116064
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Type: Journal article
Title: Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the colon cancer family registry cohort
Author: Rosty, C.
Clendenning, M.
Walsh, M.
Eriksen, S.
Southey, M.
Winship, I.
Macrae, F.
Boussioutas, A.
Poplawski, N.
Parry, S.
Arnold, J.
Young, J.
Casey, G.
Haile, R.
Gallinger, S.
Le Marchand, L.
Newcomb, P.
Potter, J.
Derycke, M.
Lindor, N.
et al.
Citation: BMJ Open, 2016; 6(2):e010293
Publisher: BMJ
Issue Date: 2016
ISSN: 2044-6055
2044-6055
Statement of
Responsibility: 
Christophe Rosty, Mark Clendenning, Michael D Walsh, Stine V Eriksen … Nicola Poplawski … Joanne Young … et al.
Abstract: Objectives: 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.
Keywords: Colon Cancer Family Registry Cohort
Rights: This 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/
RMID: 0030043424
DOI: 10.1136/bmjopen-2015-010293
Appears in Collections:Medicine publications

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