Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer

Melissa C. Southey, Mark A. Jenkins, Leeanne Mead, Jonathan Whitty, Melanie Trivett, Andrea A. Tesoriero, Letitia D. Smith, Kim Jennings, Garry Grubb, Simon G. Royce, Michael D. Walsh, Melissa A. Barker, Joanne P. Young, Jeremy R. Jass, D. James B St. John, Finlay A. Macrae, Graham G. Giles, John L. Hopper

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Abstract

Purpose: The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. 

Methods: We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, orthat lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins. 

Results: Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%. 

Conclusions: Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.

Original languageEnglish
Pages (from-to)6524-6532
Number of pages9
JournalJournal of Clinical Oncology
Volume23
Issue number27
DOIs
Publication statusPublished - 20 Sep 2005
Externally publishedYes

Cite this

Southey, Melissa C. ; Jenkins, Mark A. ; Mead, Leeanne ; Whitty, Jonathan ; Trivett, Melanie ; Tesoriero, Andrea A. ; Smith, Letitia D. ; Jennings, Kim ; Grubb, Garry ; Royce, Simon G. ; Walsh, Michael D. ; Barker, Melissa A. ; Young, Joanne P. ; Jass, Jeremy R. ; St. John, D. James B ; Macrae, Finlay A. ; Giles, Graham G. ; Hopper, John L. / Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 27. pp. 6524-6532.
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title = "Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer",
abstract = "Purpose: The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. Methods: We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, orthat lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins. Results: Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100{\%}, 94{\%}, and 50{\%}, respectively. Corresponding positive predictive values were 69{\%}, 50{\%}, and 75{\%}. Conclusions: Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.",
author = "Southey, {Melissa C.} and Jenkins, {Mark A.} and Leeanne Mead and Jonathan Whitty and Melanie Trivett and Tesoriero, {Andrea A.} and Smith, {Letitia D.} and Kim Jennings and Garry Grubb and Royce, {Simon G.} and Walsh, {Michael D.} and Barker, {Melissa A.} and Young, {Joanne P.} and Jass, {Jeremy R.} and {St. John}, {D. James B} and Macrae, {Finlay A.} and Giles, {Graham G.} and Hopper, {John L.}",
year = "2005",
month = "9",
day = "20",
doi = "10.1200/JCO.2005.04.671",
language = "English",
volume = "23",
pages = "6524--6532",
journal = "Journal of Clinical Oncology",
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Southey, MC, Jenkins, MA, Mead, L, Whitty, J, Trivett, M, Tesoriero, AA, Smith, LD, Jennings, K, Grubb, G, Royce, SG, Walsh, MD, Barker, MA, Young, JP, Jass, JR, St. John, DJB, Macrae, FA, Giles, GG & Hopper, JL 2005, 'Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer', Journal of Clinical Oncology, vol. 23, no. 27, pp. 6524-6532. https://doi.org/10.1200/JCO.2005.04.671

Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. / Southey, Melissa C.; Jenkins, Mark A.; Mead, Leeanne; Whitty, Jonathan; Trivett, Melanie; Tesoriero, Andrea A.; Smith, Letitia D.; Jennings, Kim; Grubb, Garry; Royce, Simon G.; Walsh, Michael D.; Barker, Melissa A.; Young, Joanne P.; Jass, Jeremy R.; St. John, D. James B; Macrae, Finlay A.; Giles, Graham G.; Hopper, John L.

In: Journal of Clinical Oncology, Vol. 23, No. 27, 20.09.2005, p. 6524-6532.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer

AU - Southey, Melissa C.

AU - Jenkins, Mark A.

AU - Mead, Leeanne

AU - Whitty, Jonathan

AU - Trivett, Melanie

AU - Tesoriero, Andrea A.

AU - Smith, Letitia D.

AU - Jennings, Kim

AU - Grubb, Garry

AU - Royce, Simon G.

AU - Walsh, Michael D.

AU - Barker, Melissa A.

AU - Young, Joanne P.

AU - Jass, Jeremy R.

AU - St. John, D. James B

AU - Macrae, Finlay A.

AU - Giles, Graham G.

AU - Hopper, John L.

PY - 2005/9/20

Y1 - 2005/9/20

N2 - Purpose: The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. Methods: We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, orthat lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins. Results: Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%. Conclusions: Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.

AB - Purpose: The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. Methods: We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, orthat lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins. Results: Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%. Conclusions: Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.

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U2 - 10.1200/JCO.2005.04.671

DO - 10.1200/JCO.2005.04.671

M3 - Article

VL - 23

SP - 6524

EP - 6532

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 27

ER -