Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts

on behalf of the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort investigators

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background and Aim: Tumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilizing a combination of tumor and germline testing approaches. Methods: Colorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAFV600E somatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR-deficient tumors and a subset of MMR-proficient CRCs. Results: Of the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1%), and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5%) and seven had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR-deficient CRC without MLH1 methylation and a gene mutation were considered Lynch-like and comprised 41.1% and 25.2% of the MMR-deficient CRCs for the ACCFR and MCCS, respectively. Conclusions: Identification of MMR gene mutation carriers in Australian CRC-affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR-deficient CRCs will have unknown etiology (Lynch-like) proving problematic for clinical management.

Original languageEnglish (US)
Pages (from-to)427-438
Number of pages12
JournalJournal of Gastroenterology and Hepatology (Australia)
Volume32
Issue number2
DOIs
StatePublished - Feb 1 2017

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Hereditary Nonpolyposis Colorectal Neoplasms
DNA Mismatch Repair
Colorectal Neoplasms
Neoplasms
Mutation
Genes
Registries
Cohort Studies
Germ-Line Mutation
Methylation
Immunohistochemistry
Microsatellite Instability
Multiplex Polymerase Chain Reaction

Keywords

  • Colorectal cancer
  • immunohistochemistry
  • Lynch syndrome
  • microsatellite instability, MLH1, MSH2, MSH6, PMS2, MLH1 methylation, BRAF
  • mismatch repair protein expression

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

on behalf of the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort investigators (2017). Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts. Journal of Gastroenterology and Hepatology (Australia), 32(2), 427-438. https://doi.org/10.1111/jgh.13468

Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts. / on behalf of the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort investigators.

In: Journal of Gastroenterology and Hepatology (Australia), Vol. 32, No. 2, 01.02.2017, p. 427-438.

Research output: Contribution to journalArticle

on behalf of the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort investigators 2017, 'Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts', Journal of Gastroenterology and Hepatology (Australia), vol. 32, no. 2, pp. 427-438. https://doi.org/10.1111/jgh.13468
on behalf of the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort investigators. Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts. Journal of Gastroenterology and Hepatology (Australia). 2017 Feb 1;32(2):427-438. https://doi.org/10.1111/jgh.13468
on behalf of the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort investigators. / Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts. In: Journal of Gastroenterology and Hepatology (Australia). 2017 ; Vol. 32, No. 2. pp. 427-438.
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abstract = "Background and Aim: Tumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilizing a combination of tumor and germline testing approaches. Methods: Colorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAFV600E somatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR-deficient tumors and a subset of MMR-proficient CRCs. Results: Of the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1{\%}), and 42 had a MMR gene germline mutation (5.2{\%}). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5{\%}) and seven had a germline mutation (0.8{\%}). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR-deficient CRC without MLH1 methylation and a gene mutation were considered Lynch-like and comprised 41.1{\%} and 25.2{\%} of the MMR-deficient CRCs for the ACCFR and MCCS, respectively. Conclusions: Identification of MMR gene mutation carriers in Australian CRC-affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR-deficient CRCs will have unknown etiology (Lynch-like) proving problematic for clinical management.",
keywords = "Colorectal cancer, immunohistochemistry, Lynch syndrome, microsatellite instability, MLH1, MSH2, MSH6, PMS2, MLH1 methylation, BRAF, mismatch repair protein expression",
author = "{on behalf of the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort investigators} and Buchanan, {Daniel D.} and Mark Clendenning and Christophe Rosty and Eriksen, {Stine V.} and Walsh, {Michael D.} and Walters, {Rhiannon J.} and Thibodeau, {Stephen N} and Jenna Stewart and Susan Preston and Win, {Aung Ko} and Louisa Flander and {Ait Ouakrim}, Driss and Macrae, {Finlay A.} and Alex Boussioutas and Winship, {Ingrid M.} and Giles, {Graham G.} and Hopper, {John L.} and Southey, {Melissa C.} and Dallas English and Jenkins, {Mark A.}",
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T1 - Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts

AU - on behalf of the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort investigators

AU - Buchanan, Daniel D.

AU - Clendenning, Mark

AU - Rosty, Christophe

AU - Eriksen, Stine V.

AU - Walsh, Michael D.

AU - Walters, Rhiannon J.

AU - Thibodeau, Stephen N

AU - Stewart, Jenna

AU - Preston, Susan

AU - Win, Aung Ko

AU - Flander, Louisa

AU - Ait Ouakrim, Driss

AU - Macrae, Finlay A.

AU - Boussioutas, Alex

AU - Winship, Ingrid M.

AU - Giles, Graham G.

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - English, Dallas

AU - Jenkins, Mark A.

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Background and Aim: Tumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilizing a combination of tumor and germline testing approaches. Methods: Colorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAFV600E somatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR-deficient tumors and a subset of MMR-proficient CRCs. Results: Of the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1%), and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5%) and seven had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR-deficient CRC without MLH1 methylation and a gene mutation were considered Lynch-like and comprised 41.1% and 25.2% of the MMR-deficient CRCs for the ACCFR and MCCS, respectively. Conclusions: Identification of MMR gene mutation carriers in Australian CRC-affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR-deficient CRCs will have unknown etiology (Lynch-like) proving problematic for clinical management.

AB - Background and Aim: Tumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilizing a combination of tumor and germline testing approaches. Methods: Colorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAFV600E somatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR-deficient tumors and a subset of MMR-proficient CRCs. Results: Of the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1%), and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5%) and seven had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR-deficient CRC without MLH1 methylation and a gene mutation were considered Lynch-like and comprised 41.1% and 25.2% of the MMR-deficient CRCs for the ACCFR and MCCS, respectively. Conclusions: Identification of MMR gene mutation carriers in Australian CRC-affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR-deficient CRCs will have unknown etiology (Lynch-like) proving problematic for clinical management.

KW - Colorectal cancer

KW - immunohistochemistry

KW - Lynch syndrome

KW - microsatellite instability, MLH1, MSH2, MSH6, PMS2, MLH1 methylation, BRAF

KW - mismatch repair protein expression

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