Microsatellite instability accounts for tumor site-related differences in clinicopathologic variables and prognosis in human colon cancers

Frank A Sinicrope, Rafaela L. Rego, Nathan Foster, Daniel J. Sargent, Harold E. Windschitl, Lawrence J. Burgart, Thomas Elmer Witzig, Stephen N Thibodeau

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: Colon cancers with high frequency microsatellite instability (MSI-H) are preferentially located in the proximal colon. Given that 15-20% of sporadic colon cancers are MSI-H, we determined whether tumor site-specific differences in clinicopathological variables, biomarkers, and prognosis are due to inclusion of MSI-H cases. METHODS: TNM stage II and III primary colon carcinomas (N = 528) from patients enrolled in 5-fluorouracil-based adjuvant trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for DNA mismatch repair (hMLH1, hMSH2, hMSH6) and p53 proteins was performed. DNA ploidy (diploid vs aneuploid/tetraploid) and proliferative indices (PI: S-phase + G2M) were analyzed by flow cytometry. RESULTS: MSI-H was found in 95 (18%) colon cancers. Proximal tumors (N = 286) were associated with MSI-H, older age (>65 yr), poor differentiation, and diploid DNA content compared with distal tumors (all P ≤ 0.016). Nuclear p53 staining was more frequent in distal tumors (P = 0.002); PI was unrelated to tumor site. When MSI-H tumors were excluded, no tumor site-related differences were found except for age, which remained associated with proximal cancers (P = 0.030). Proximal site was associated with improved disease-free survival in all patients (P = 0.042), but not when MSI-H cases were excluded (P = 0.236). MSI-H status or loss of mismatch repair proteins, diploidy, and lower PI were associated with improved survival rates. CONCLUSIONS: Tumor site-related differences in clinicopathological variables, biomarkers, and prognosis of sporadic colon cancers can be explained by the inclusion of MSI-H cases. Older age, however, is associated with proximal tumor site independent of MSI status.

Original languageEnglish (US)
Pages (from-to)2818-2825
Number of pages8
JournalAmerican Journal of Gastroenterology
Volume101
Issue number12
DOIs
StatePublished - Dec 2006

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Microsatellite Instability
Colonic Neoplasms
Neoplasms
Diploidy
DNA Mismatch Repair
Colon
N-methylsuccinimide
Biomarkers
Tetraploidy
Ploidies
DNA
Aneuploidy
S Phase
Fluorouracil
Microsatellite Repeats
Disease-Free Survival
Flow Cytometry
Proteins
Survival Rate
Staining and Labeling

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Microsatellite instability accounts for tumor site-related differences in clinicopathologic variables and prognosis in human colon cancers. / Sinicrope, Frank A; Rego, Rafaela L.; Foster, Nathan; Sargent, Daniel J.; Windschitl, Harold E.; Burgart, Lawrence J.; Witzig, Thomas Elmer; Thibodeau, Stephen N.

In: American Journal of Gastroenterology, Vol. 101, No. 12, 12.2006, p. 2818-2825.

Research output: Contribution to journalArticle

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abstract = "OBJECTIVE: Colon cancers with high frequency microsatellite instability (MSI-H) are preferentially located in the proximal colon. Given that 15-20{\%} of sporadic colon cancers are MSI-H, we determined whether tumor site-specific differences in clinicopathological variables, biomarkers, and prognosis are due to inclusion of MSI-H cases. METHODS: TNM stage II and III primary colon carcinomas (N = 528) from patients enrolled in 5-fluorouracil-based adjuvant trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for DNA mismatch repair (hMLH1, hMSH2, hMSH6) and p53 proteins was performed. DNA ploidy (diploid vs aneuploid/tetraploid) and proliferative indices (PI: S-phase + G2M) were analyzed by flow cytometry. RESULTS: MSI-H was found in 95 (18{\%}) colon cancers. Proximal tumors (N = 286) were associated with MSI-H, older age (>65 yr), poor differentiation, and diploid DNA content compared with distal tumors (all P ≤ 0.016). Nuclear p53 staining was more frequent in distal tumors (P = 0.002); PI was unrelated to tumor site. When MSI-H tumors were excluded, no tumor site-related differences were found except for age, which remained associated with proximal cancers (P = 0.030). Proximal site was associated with improved disease-free survival in all patients (P = 0.042), but not when MSI-H cases were excluded (P = 0.236). MSI-H status or loss of mismatch repair proteins, diploidy, and lower PI were associated with improved survival rates. CONCLUSIONS: Tumor site-related differences in clinicopathological variables, biomarkers, and prognosis of sporadic colon cancers can be explained by the inclusion of MSI-H cases. Older age, however, is associated with proximal tumor site independent of MSI status.",
author = "Sinicrope, {Frank A} and Rego, {Rafaela L.} and Nathan Foster and Sargent, {Daniel J.} and Windschitl, {Harold E.} and Burgart, {Lawrence J.} and Witzig, {Thomas Elmer} and Thibodeau, {Stephen N}",
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T1 - Microsatellite instability accounts for tumor site-related differences in clinicopathologic variables and prognosis in human colon cancers

AU - Sinicrope, Frank A

AU - Rego, Rafaela L.

AU - Foster, Nathan

AU - Sargent, Daniel J.

AU - Windschitl, Harold E.

AU - Burgart, Lawrence J.

AU - Witzig, Thomas Elmer

AU - Thibodeau, Stephen N

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N2 - OBJECTIVE: Colon cancers with high frequency microsatellite instability (MSI-H) are preferentially located in the proximal colon. Given that 15-20% of sporadic colon cancers are MSI-H, we determined whether tumor site-specific differences in clinicopathological variables, biomarkers, and prognosis are due to inclusion of MSI-H cases. METHODS: TNM stage II and III primary colon carcinomas (N = 528) from patients enrolled in 5-fluorouracil-based adjuvant trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for DNA mismatch repair (hMLH1, hMSH2, hMSH6) and p53 proteins was performed. DNA ploidy (diploid vs aneuploid/tetraploid) and proliferative indices (PI: S-phase + G2M) were analyzed by flow cytometry. RESULTS: MSI-H was found in 95 (18%) colon cancers. Proximal tumors (N = 286) were associated with MSI-H, older age (>65 yr), poor differentiation, and diploid DNA content compared with distal tumors (all P ≤ 0.016). Nuclear p53 staining was more frequent in distal tumors (P = 0.002); PI was unrelated to tumor site. When MSI-H tumors were excluded, no tumor site-related differences were found except for age, which remained associated with proximal cancers (P = 0.030). Proximal site was associated with improved disease-free survival in all patients (P = 0.042), but not when MSI-H cases were excluded (P = 0.236). MSI-H status or loss of mismatch repair proteins, diploidy, and lower PI were associated with improved survival rates. CONCLUSIONS: Tumor site-related differences in clinicopathological variables, biomarkers, and prognosis of sporadic colon cancers can be explained by the inclusion of MSI-H cases. Older age, however, is associated with proximal tumor site independent of MSI status.

AB - OBJECTIVE: Colon cancers with high frequency microsatellite instability (MSI-H) are preferentially located in the proximal colon. Given that 15-20% of sporadic colon cancers are MSI-H, we determined whether tumor site-specific differences in clinicopathological variables, biomarkers, and prognosis are due to inclusion of MSI-H cases. METHODS: TNM stage II and III primary colon carcinomas (N = 528) from patients enrolled in 5-fluorouracil-based adjuvant trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for DNA mismatch repair (hMLH1, hMSH2, hMSH6) and p53 proteins was performed. DNA ploidy (diploid vs aneuploid/tetraploid) and proliferative indices (PI: S-phase + G2M) were analyzed by flow cytometry. RESULTS: MSI-H was found in 95 (18%) colon cancers. Proximal tumors (N = 286) were associated with MSI-H, older age (>65 yr), poor differentiation, and diploid DNA content compared with distal tumors (all P ≤ 0.016). Nuclear p53 staining was more frequent in distal tumors (P = 0.002); PI was unrelated to tumor site. When MSI-H tumors were excluded, no tumor site-related differences were found except for age, which remained associated with proximal cancers (P = 0.030). Proximal site was associated with improved disease-free survival in all patients (P = 0.042), but not when MSI-H cases were excluded (P = 0.236). MSI-H status or loss of mismatch repair proteins, diploidy, and lower PI were associated with improved survival rates. CONCLUSIONS: Tumor site-related differences in clinicopathological variables, biomarkers, and prognosis of sporadic colon cancers can be explained by the inclusion of MSI-H cases. Older age, however, is associated with proximal tumor site independent of MSI status.

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