Prognostic Impact of Microsatellite Instability and DNA Ploidy in Human Colon Carcinoma Patients

Frank A. Sinicrope; Rafaela L. Rego; Kevin C. Halling; Nathan Foster; Daniel J. Sargent; Betsy La Plant; Amy J. French; John A. Laurie; Richard M. Goldberg; Stephen N. Thibodeau; Thomas E. Witzig

doi:10.1053/j.gastro.2006.06.005

Prognostic Impact of Microsatellite Instability and DNA Ploidy in Human Colon Carcinoma Patients

Frank A. Sinicrope, Rafaela L. Rego, Kevin C. Halling, Nathan Foster, Daniel J. Sargent, Betsy La Plant, Amy J. French, John A. Laurie, Richard M. Goldberg, Stephen N. Thibodeau, Thomas E. Witzig

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183 Scopus citations

Abstract

Background & Aims: Genomic instability in colon cancers is a consequence of chromosomal instability characterized by aneuploidy or defective DNA mismatch repair (MMR) indicated by microsatellite instability (MSI). Given that high-frequency MSI (MSI-H) and diploidy are correlated, we determined whether they are independent prognostic variables. Methods: Astler-Coller stage B2 and C colon cancers (N = 528) from patients treated in 5-fluorouracil-based adjuvant therapy trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for hMLH1, hMSH2, and p53 proteins was performed. DNA ploidy was analyzed by flow cytometry. Associations with disease-free and overall survival were determined. Results: MSI-H was detected in 95 tumors (18%), and 70 (74%) of these were diploid. Tumors showing MSI-H (hazard ratio, 0.65; 95% confidence interval, 0.44-0.96; P = .023) or loss of MMR proteins (P = .024) were associated with better overall survival. Improved disease-free and overall survival were found for diploid versus aneuploid/tetraploid tumors (overall survival: hazard ratio, 0.59; 95% confidence interval, 0.43-0.79; P = .0003). In the subgroups of MSI-H and microsatellite stable (MSS)/low-frequency MSI (MSI-L) tumors, diploidy was associated with better survival. The prognostic impact of ploidy was similar in stage B2 and C tumors. Ploidy did not predict the benefit of 5-fluorouracil-based treatment. When ploidy, MSI, and MMR proteins were analyzed in the same multivariate model, only ploidy remained significant. Conclusions: DNA ploidy and MSI-H status were independent prognostic variables, yet ploidy was the strongest marker. Diploidy was associated with better survival in MSI-H and in MSS/MSI-L patient subgroups.

Original language	English (US)
Pages (from-to)	729-737
Number of pages	9
Journal	Gastroenterology
Volume	131
Issue number	3
DOIs	https://doi.org/10.1053/j.gastro.2006.06.005
State	Published - Sep 2006

ASJC Scopus subject areas

Hepatology
Gastroenterology

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@article{7f28e01ea0764c54b4d58be2a76b01f2,

title = "Prognostic Impact of Microsatellite Instability and DNA Ploidy in Human Colon Carcinoma Patients",

abstract = "Background & Aims: Genomic instability in colon cancers is a consequence of chromosomal instability characterized by aneuploidy or defective DNA mismatch repair (MMR) indicated by microsatellite instability (MSI). Given that high-frequency MSI (MSI-H) and diploidy are correlated, we determined whether they are independent prognostic variables. Methods: Astler-Coller stage B2 and C colon cancers (N = 528) from patients treated in 5-fluorouracil-based adjuvant therapy trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for hMLH1, hMSH2, and p53 proteins was performed. DNA ploidy was analyzed by flow cytometry. Associations with disease-free and overall survival were determined. Results: MSI-H was detected in 95 tumors (18%), and 70 (74%) of these were diploid. Tumors showing MSI-H (hazard ratio, 0.65; 95% confidence interval, 0.44-0.96; P = .023) or loss of MMR proteins (P = .024) were associated with better overall survival. Improved disease-free and overall survival were found for diploid versus aneuploid/tetraploid tumors (overall survival: hazard ratio, 0.59; 95% confidence interval, 0.43-0.79; P = .0003). In the subgroups of MSI-H and microsatellite stable (MSS)/low-frequency MSI (MSI-L) tumors, diploidy was associated with better survival. The prognostic impact of ploidy was similar in stage B2 and C tumors. Ploidy did not predict the benefit of 5-fluorouracil-based treatment. When ploidy, MSI, and MMR proteins were analyzed in the same multivariate model, only ploidy remained significant. Conclusions: DNA ploidy and MSI-H status were independent prognostic variables, yet ploidy was the strongest marker. Diploidy was associated with better survival in MSI-H and in MSS/MSI-L patient subgroups.",

author = "Sinicrope, {Frank A.} and Rego, {Rafaela L.} and Halling, {Kevin C.} and Nathan Foster and Sargent, {Daniel J.} and {La Plant}, Betsy and French, {Amy J.} and Laurie, {John A.} and Goldberg, {Richard M.} and Thibodeau, {Stephen N.} and Witzig, {Thomas E.}",

note = "Funding Information: Supported in part by a grant from the National Institutes of Health/National Cancer Institute CA 104683 (to F.A.S.). Clinical–alimentary tract ",

year = "2006",

month = sep,

doi = "10.1053/j.gastro.2006.06.005",

language = "English (US)",

volume = "131",

pages = "729--737",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "3",

}

TY - JOUR

T1 - Prognostic Impact of Microsatellite Instability and DNA Ploidy in Human Colon Carcinoma Patients

AU - Sinicrope, Frank A.

AU - Rego, Rafaela L.

AU - Halling, Kevin C.

AU - Foster, Nathan

AU - Sargent, Daniel J.

AU - La Plant, Betsy

AU - French, Amy J.

AU - Laurie, John A.

AU - Goldberg, Richard M.

AU - Thibodeau, Stephen N.

AU - Witzig, Thomas E.

N1 - Funding Information: Supported in part by a grant from the National Institutes of Health/National Cancer Institute CA 104683 (to F.A.S.). Clinical–alimentary tract

PY - 2006/9

Y1 - 2006/9

N2 - Background & Aims: Genomic instability in colon cancers is a consequence of chromosomal instability characterized by aneuploidy or defective DNA mismatch repair (MMR) indicated by microsatellite instability (MSI). Given that high-frequency MSI (MSI-H) and diploidy are correlated, we determined whether they are independent prognostic variables. Methods: Astler-Coller stage B2 and C colon cancers (N = 528) from patients treated in 5-fluorouracil-based adjuvant therapy trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for hMLH1, hMSH2, and p53 proteins was performed. DNA ploidy was analyzed by flow cytometry. Associations with disease-free and overall survival were determined. Results: MSI-H was detected in 95 tumors (18%), and 70 (74%) of these were diploid. Tumors showing MSI-H (hazard ratio, 0.65; 95% confidence interval, 0.44-0.96; P = .023) or loss of MMR proteins (P = .024) were associated with better overall survival. Improved disease-free and overall survival were found for diploid versus aneuploid/tetraploid tumors (overall survival: hazard ratio, 0.59; 95% confidence interval, 0.43-0.79; P = .0003). In the subgroups of MSI-H and microsatellite stable (MSS)/low-frequency MSI (MSI-L) tumors, diploidy was associated with better survival. The prognostic impact of ploidy was similar in stage B2 and C tumors. Ploidy did not predict the benefit of 5-fluorouracil-based treatment. When ploidy, MSI, and MMR proteins were analyzed in the same multivariate model, only ploidy remained significant. Conclusions: DNA ploidy and MSI-H status were independent prognostic variables, yet ploidy was the strongest marker. Diploidy was associated with better survival in MSI-H and in MSS/MSI-L patient subgroups.

AB - Background & Aims: Genomic instability in colon cancers is a consequence of chromosomal instability characterized by aneuploidy or defective DNA mismatch repair (MMR) indicated by microsatellite instability (MSI). Given that high-frequency MSI (MSI-H) and diploidy are correlated, we determined whether they are independent prognostic variables. Methods: Astler-Coller stage B2 and C colon cancers (N = 528) from patients treated in 5-fluorouracil-based adjuvant therapy trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for hMLH1, hMSH2, and p53 proteins was performed. DNA ploidy was analyzed by flow cytometry. Associations with disease-free and overall survival were determined. Results: MSI-H was detected in 95 tumors (18%), and 70 (74%) of these were diploid. Tumors showing MSI-H (hazard ratio, 0.65; 95% confidence interval, 0.44-0.96; P = .023) or loss of MMR proteins (P = .024) were associated with better overall survival. Improved disease-free and overall survival were found for diploid versus aneuploid/tetraploid tumors (overall survival: hazard ratio, 0.59; 95% confidence interval, 0.43-0.79; P = .0003). In the subgroups of MSI-H and microsatellite stable (MSS)/low-frequency MSI (MSI-L) tumors, diploidy was associated with better survival. The prognostic impact of ploidy was similar in stage B2 and C tumors. Ploidy did not predict the benefit of 5-fluorouracil-based treatment. When ploidy, MSI, and MMR proteins were analyzed in the same multivariate model, only ploidy remained significant. Conclusions: DNA ploidy and MSI-H status were independent prognostic variables, yet ploidy was the strongest marker. Diploidy was associated with better survival in MSI-H and in MSS/MSI-L patient subgroups.

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ER -

Prognostic Impact of Microsatellite Instability and DNA Ploidy in Human Colon Carcinoma Patients

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