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

doi:10.1053/j.gastro.2006.06.005

Gastroenterology

Volume 131, Issue 3, September 2006, Pages 729-737

https://doi.org/10.1053/j.gastro.2006.06.005 Get rights and content

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.

Section snippets

Patients and Methods

Data were obtained from 6 randomized 5-FU–based phase 3 adjuvant studies conducted by the North Central Cancer Treatment Group. Paraffin-embedded tumor tissue specimens were available from study participants. Tumors were staged according to the Astler–Coller modification of the Dukes’ classification²⁶ and included stage B2 (n = 158) and C (n = 370) colon cancers (N = 528). Tumor histologic grade was defined²⁷ as follows: grade 1, well differentiated; grade 2, moderately differentiated; grade 3,

Results

The molecular and phenotypic features of colon cancers arising from the chromosomal instability and MSI pathways may be useful for prognostication. Colon cancers with MSI-H are frequently diploid and have been shown to have a better prognosis compared with MSS/MSI-L tumors.6, 13, 16, 17 Therefore, we sought to determine whether MSI and ploidy are independent prognostic variables or whether diploidy accounts for or contributes to the favorable outcome of MSI-H colon cancers.

Discussion

The hallmark of the chromosomal instability pathway is aneuploidy and that of the MSI pathway is defective DNA MMR. We found that aneuploid/tetraploid DNA content was associated with higher tumor stage and poorer differentiation, distal tumor site, and nuclear p53 expression as compared with diploidy. In addition, these aneuploid/tetraploid tumors were generally MSS/MSI-L. Among patients with Astler–Coller B2 and C colon cancers participating in these adjuvant studies, 18% of tumors were MSI-H

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: Supported in part by a grant from the National Institutes of Health/National Cancer Institute CA 104683 (to F.A.S.).

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Clinical–alimentary tractPrognostic Impact of Microsatellite Instability and DNA Ploidy in Human Colon Carcinoma Patients

Section snippets

Patients and Methods

Results

Discussion

Cell

Gastroenterology

Am J Pathol

Mod Pathol

Am J Hum Genet

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

cancer statistics, 2004

CA Cancer

Genetic instability in colorectal cancers

Nature

Mutations of mitotic checkpoint genes in human cancers

Nature

Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis

Nature

Microsatellite instability in cancer of the proximal colon

Science

Characterization of sporadic colon cancer by patterns of genomic instability

Cancer Res

Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability

Cancer Res

Epigenetic phenotypes distinguish microsatellite-stable and -unstable colorectal cancers

Proc Natl Acad Sci U S A

Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors

J Clin Oncol

Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history

Cancer Res

A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer

Cancer Res

Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1

Cancer Res

Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers

J Natl Cancer Inst

Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer

N Engl J Med

Clinical–alimentary tract
Prognostic Impact of Microsatellite Instability and DNA Ploidy in Human Colon Carcinoma Patients