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

Rosty, Christophe, Clendenning, Mark, Walsh, Michael D., Eriksen, Stine V., Southey, Melissa C., Winship, Ingrid M., Macrae, Finlay A., Boussioutas, Alex, Poplawski, Nicola K., Parry, Susan, Arnold, Julie, Young, Joanne P., Casey, Graham, Haile, Robert W., Gallinger, Steven, Le Marchand, Loic, Newcomb, Polly A., Potter, John D., Derycke, Melissa, Lindor, Noralane M., Thibodeau, Stephen N., Baron, John A., Win, Aung Ko, Hopper, John L., Jenkins, Mark A. and Buchanan, Daniel D. (2016) Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the colon cancer family registry cohort. BMJ Open, 6 2: . doi:10.1136/bmjopen-2015-010293


Author Rosty, Christophe
Clendenning, Mark
Walsh, Michael D.
Eriksen, Stine V.
Southey, Melissa C.
Winship, Ingrid M.
Macrae, Finlay A.
Boussioutas, Alex
Poplawski, Nicola K.
Parry, Susan
Arnold, Julie
Young, Joanne P.
Casey, Graham
Haile, Robert W.
Gallinger, Steven
Le Marchand, Loic
Newcomb, Polly A.
Potter, John D.
Derycke, Melissa
Lindor, Noralane M.
Thibodeau, Stephen N.
Baron, John A.
Win, Aung Ko
Hopper, John L.
Jenkins, Mark A.
Buchanan, Daniel D.
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
Formatted 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
Journal name BMJ Open   Check publisher's open access policy
ISSN 2044-6055
Publication date 2016-02-19
Year available 2016
Sub-type Article (original research)
DOI 10.1136/bmjopen-2015-010293
Open Access Status DOI
Volume 6
Issue 2
Total pages 9
Place of publication London, United Kingdom
Publisher BMJ Group
Language eng
Formatted 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.Gln197Argfs8 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.
Keyword Colorectal carcinoma (CRC)
PMS2
MLH1 mutation
DNA mismatch repair (MMR) gene
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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