Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes

Leeanne J. Mead, Mark A. Jenkins, Joanne Young, Simon G. Royce, Letitia Smith, D. James B St. John, Finlay Macrae, Graham G. Giles, John L. Hopper, Melissa C. Southey

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Abstract

Purpose: Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes. 

Experimental Design: Invasive primary tumors from a population-based sample of 107 cases of colorectal cancer diagnosed before age 45 years and tested for germ-line mutations in MLHI, MSH2, MSH6, and PMS2 and MMR protein expression were screened for MSI using the National Cancer Institute panel and an expanded 10-microsatellite marker panel. 

Results: The National Cancer Institute five-marker panel system scored 31 (29%) as NCIMSI-High, 13 (12%) as NCIMSI-Low, and 63 (59%) as NCIMS-Stable. The 10-marker panel classified 18 (17%) as 10MSI-High, 17 (16%) as 10MSI-Low, and 72 (67%) as 10MS-Stable. Of the 26 cancers that lacked the expression of at least one MMR gene, 24 (92%) were positive for some level of MSI (using either microsatellite panel). The mononucleotide repeats Bat26, Bat40, and Myb were unstable in all 10MSI-High cancers and all MLHI and MSH2 mutation carriers (100% sensitive). Bat40 and Bat25 were unstable in all tumors of MSH6 mutation carriers (100% sensitive). Bat40 was unstable in all MMR gene mutation carriers (100% sensitive). By incorporating seven mononucleotide repeats markers into the 10-marker panel, we were able to distinguish the carriers of MSH6 mutations (all scored 10MSI-Low) from the MLHI and MSH2 mutation carriers (all scored 10MSI-High). 

Conclusions: In early-onset colorectal cancer, a microsatellite panel containing a high proportion of mononuclear repeats can distinguish between tumors caused by MLH1 and MSH2 mutations from those caused by MSH6 mutations.

Original languageEnglish
Pages (from-to)2865-2869
Number of pages5
JournalClinical Cancer Research
Volume13
Issue number10
DOIs
Publication statusPublished - 15 May 2007
Externally publishedYes

Cite this

Mead, Leeanne J. ; Jenkins, Mark A. ; Young, Joanne ; Royce, Simon G. ; Smith, Letitia ; St. John, D. James B ; Macrae, Finlay ; Giles, Graham G. ; Hopper, John L. ; Southey, Melissa C. / Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 10. pp. 2865-2869.
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title = "Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes",
abstract = "Purpose: Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes. Experimental Design: Invasive primary tumors from a population-based sample of 107 cases of colorectal cancer diagnosed before age 45 years and tested for germ-line mutations in MLHI, MSH2, MSH6, and PMS2 and MMR protein expression were screened for MSI using the National Cancer Institute panel and an expanded 10-microsatellite marker panel. Results: The National Cancer Institute five-marker panel system scored 31 (29{\%}) as NCIMSI-High, 13 (12{\%}) as NCIMSI-Low, and 63 (59{\%}) as NCIMS-Stable. The 10-marker panel classified 18 (17{\%}) as 10MSI-High, 17 (16{\%}) as 10MSI-Low, and 72 (67{\%}) as 10MS-Stable. Of the 26 cancers that lacked the expression of at least one MMR gene, 24 (92{\%}) were positive for some level of MSI (using either microsatellite panel). The mononucleotide repeats Bat26, Bat40, and Myb were unstable in all 10MSI-High cancers and all MLHI and MSH2 mutation carriers (100{\%} sensitive). Bat40 and Bat25 were unstable in all tumors of MSH6 mutation carriers (100{\%} sensitive). Bat40 was unstable in all MMR gene mutation carriers (100{\%} sensitive). By incorporating seven mononucleotide repeats markers into the 10-marker panel, we were able to distinguish the carriers of MSH6 mutations (all scored 10MSI-Low) from the MLHI and MSH2 mutation carriers (all scored 10MSI-High). Conclusions: In early-onset colorectal cancer, a microsatellite panel containing a high proportion of mononuclear repeats can distinguish between tumors caused by MLH1 and MSH2 mutations from those caused by MSH6 mutations.",
author = "Mead, {Leeanne J.} and Jenkins, {Mark A.} and Joanne Young and Royce, {Simon G.} and Letitia Smith and {St. John}, {D. James B} and Finlay Macrae and Giles, {Graham G.} and Hopper, {John L.} and Southey, {Melissa C.}",
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Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes. / Mead, Leeanne J.; Jenkins, Mark A.; Young, Joanne; Royce, Simon G.; Smith, Letitia; St. John, D. James B; Macrae, Finlay; Giles, Graham G.; Hopper, John L.; Southey, Melissa C.

In: Clinical Cancer Research, Vol. 13, No. 10, 15.05.2007, p. 2865-2869.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes

AU - Mead, Leeanne J.

AU - Jenkins, Mark A.

AU - Young, Joanne

AU - Royce, Simon G.

AU - Smith, Letitia

AU - St. John, D. James B

AU - Macrae, Finlay

AU - Giles, Graham G.

AU - Hopper, John L.

AU - Southey, Melissa C.

PY - 2007/5/15

Y1 - 2007/5/15

N2 - Purpose: Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes. Experimental Design: Invasive primary tumors from a population-based sample of 107 cases of colorectal cancer diagnosed before age 45 years and tested for germ-line mutations in MLHI, MSH2, MSH6, and PMS2 and MMR protein expression were screened for MSI using the National Cancer Institute panel and an expanded 10-microsatellite marker panel. Results: The National Cancer Institute five-marker panel system scored 31 (29%) as NCIMSI-High, 13 (12%) as NCIMSI-Low, and 63 (59%) as NCIMS-Stable. The 10-marker panel classified 18 (17%) as 10MSI-High, 17 (16%) as 10MSI-Low, and 72 (67%) as 10MS-Stable. Of the 26 cancers that lacked the expression of at least one MMR gene, 24 (92%) were positive for some level of MSI (using either microsatellite panel). The mononucleotide repeats Bat26, Bat40, and Myb were unstable in all 10MSI-High cancers and all MLHI and MSH2 mutation carriers (100% sensitive). Bat40 and Bat25 were unstable in all tumors of MSH6 mutation carriers (100% sensitive). Bat40 was unstable in all MMR gene mutation carriers (100% sensitive). By incorporating seven mononucleotide repeats markers into the 10-marker panel, we were able to distinguish the carriers of MSH6 mutations (all scored 10MSI-Low) from the MLHI and MSH2 mutation carriers (all scored 10MSI-High). Conclusions: In early-onset colorectal cancer, a microsatellite panel containing a high proportion of mononuclear repeats can distinguish between tumors caused by MLH1 and MSH2 mutations from those caused by MSH6 mutations.

AB - Purpose: Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes. Experimental Design: Invasive primary tumors from a population-based sample of 107 cases of colorectal cancer diagnosed before age 45 years and tested for germ-line mutations in MLHI, MSH2, MSH6, and PMS2 and MMR protein expression were screened for MSI using the National Cancer Institute panel and an expanded 10-microsatellite marker panel. Results: The National Cancer Institute five-marker panel system scored 31 (29%) as NCIMSI-High, 13 (12%) as NCIMSI-Low, and 63 (59%) as NCIMS-Stable. The 10-marker panel classified 18 (17%) as 10MSI-High, 17 (16%) as 10MSI-Low, and 72 (67%) as 10MS-Stable. Of the 26 cancers that lacked the expression of at least one MMR gene, 24 (92%) were positive for some level of MSI (using either microsatellite panel). The mononucleotide repeats Bat26, Bat40, and Myb were unstable in all 10MSI-High cancers and all MLHI and MSH2 mutation carriers (100% sensitive). Bat40 and Bat25 were unstable in all tumors of MSH6 mutation carriers (100% sensitive). Bat40 was unstable in all MMR gene mutation carriers (100% sensitive). By incorporating seven mononucleotide repeats markers into the 10-marker panel, we were able to distinguish the carriers of MSH6 mutations (all scored 10MSI-Low) from the MLHI and MSH2 mutation carriers (all scored 10MSI-High). Conclusions: In early-onset colorectal cancer, a microsatellite panel containing a high proportion of mononuclear repeats can distinguish between tumors caused by MLH1 and MSH2 mutations from those caused by MSH6 mutations.

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