Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/116064
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
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-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/ |
DOI: | 10.1136/bmjopen-2015-010293 |
Published version: | http://dx.doi.org/10.1136/bmjopen-2015-010293 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
hdl_116064.pdf | Published version | 739.92 kB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.