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

Christophe Rosty, Mark Clendenning, Michael D. Walsh, Stine V. Eriksen, Melissa C. Southey, Ingrid M. Winship, Finlay A. Macrae, Alex Boussioutas, Nicola K. Poplawski, Susan Parry, Julie Arnold, Joanne P. Young, Graham Casey, Robert W. Haile, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, John D. Potter, Melissa Derycke, Noralane Morey LindorStephen N Thibodeau, John A. Baron, Aung Ko Win, John L. Hopper, Mark A. Jenkins, Daniel D. Buchanan

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere010293
JournalBMJ Open
Volume6
Issue number2
DOIs
StatePublished - 2016

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Germ-Line Mutation
Colonic Neoplasms
Registries
Colorectal Neoplasms
Mutation
Multiplex Polymerase Chain Reaction
Hereditary Nonpolyposis Colorectal Neoplasms
DNA Mismatch Repair
Missense Mutation
Point Mutation
Computer Simulation
Exons
Neoplasms
Cohort Studies
Immunohistochemistry
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Medicine(all)

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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, Loïc; Newcomb, Polly A.; Potter, John D.; Derycke, Melissa; Lindor, Noralane Morey; Thibodeau, Stephen N; Baron, John A.; Win, Aung Ko; Hopper, John L.; Jenkins, Mark A.; Buchanan, Daniel D.

In: BMJ Open, Vol. 6, No. 2, e010293, 2016.

Research output: Contribution to journalArticle

Rosty, C, Clendenning, M, Walsh, MD, Eriksen, SV, Southey, MC, Winship, IM, Macrae, FA, Boussioutas, A, Poplawski, NK, Parry, S, Arnold, J, Young, JP, Casey, G, Haile, RW, Gallinger, S, Le Marchand, L, Newcomb, PA, Potter, JD, Derycke, M, Lindor, NM, Thibodeau, SN, Baron, JA, Win, AK, Hopper, JL, Jenkins, MA & Buchanan, DD 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, vol. 6, no. 2, e010293. https://doi.org/10.1136/bmjopen-2015-010293
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, Loïc ; Newcomb, Polly A. ; Potter, John D. ; Derycke, Melissa ; Lindor, Noralane Morey ; Thibodeau, Stephen N ; Baron, John A. ; Win, Aung Ko ; Hopper, John L. ; Jenkins, Mark A. ; Buchanan, Daniel D. / Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the colon cancer family registry cohort. In: BMJ Open. 2016 ; Vol. 6, No. 2.
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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",
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.",
author = "Christophe Rosty and Mark Clendenning and Walsh, {Michael D.} and Eriksen, {Stine V.} and Southey, {Melissa C.} and Winship, {Ingrid M.} and Macrae, {Finlay A.} and Alex Boussioutas and Poplawski, {Nicola K.} and Susan Parry and Julie Arnold and Young, {Joanne P.} and Graham Casey and Haile, {Robert W.} and Steven Gallinger and {Le Marchand}, Lo{\"i}c and Newcomb, {Polly A.} and Potter, {John D.} and Melissa Derycke and Lindor, {Noralane Morey} and Thibodeau, {Stephen N} and Baron, {John A.} and Win, {Aung Ko} and Hopper, {John L.} and Jenkins, {Mark A.} and Buchanan, {Daniel D.}",
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T1 - Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the colon cancer family registry cohort

AU - Rosty, Christophe

AU - Clendenning, Mark

AU - Walsh, Michael D.

AU - Eriksen, Stine V.

AU - Southey, Melissa C.

AU - Winship, Ingrid M.

AU - Macrae, Finlay A.

AU - Boussioutas, Alex

AU - Poplawski, Nicola K.

AU - Parry, Susan

AU - Arnold, Julie

AU - Young, Joanne P.

AU - Casey, Graham

AU - Haile, Robert W.

AU - Gallinger, Steven

AU - Le Marchand, Loïc

AU - Newcomb, Polly A.

AU - Potter, John D.

AU - Derycke, Melissa

AU - Lindor, Noralane Morey

AU - Thibodeau, Stephen N

AU - Baron, John A.

AU - Win, Aung Ko

AU - Hopper, John L.

AU - Jenkins, Mark A.

AU - Buchanan, Daniel D.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

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