Faculty Collaboration Database

Microsatellite instability in sporadic endometrial carcinoma. J Natl Cancer Inst 1994 Aug 17;86(16):1216-21

Date

08/17/1994

Pubmed ID

8040889

DOI

10.1093/jnci/86.16.1216

Scopus ID

2-s2.0-0027992159 (requires institutional sign-in at Scopus site)   190 Citations

Abstract

BACKGROUND: Recent studies have demonstrated ubiquitous somatic microsatellite mutations in some cancers of the colon, endometrium, stomach, and pancreas.

PURPOSE: Our purpose was to characterize the frequency and nature of this replication error (RER) or mutator phenotype in sporadic endometrial carcinoma.

METHODS: Formalin-fixed, paraffin-embedded normal and tumor tissues from 45 patients with sporadic endometrial cancer were screened for the RER phenotype at three microsatellite loci. To further characterize when these alterations were acquired relative to clonal expansion, the sizes of the altered microsatellites in different tumor and normal regions were determined using selective UV radiation fractionation. Approximately 150-300 histologically defined cells on stained tissue sections were covered with small ink dots, and UV irradiation was used to destroy the DNA of cells not covered by ink. Undamaged DNA from seven to 25 spots per section were extracted, then analyzed at the Mfd27, Mfd41, and Mfd47 microsatellite loci and also at the c-K-ras gene locus with individual polymerase chain reactions. Radioactively labeled amplified DNAs were analyzed by electrophoresis and autoradiography. Fisher's exact test and the logrank test were used for statistical analysis.

RESULTS: The RER positive (RER+) phenotype was detected in nine (20%) of 45 sporadic endometrial carcinomas. The topographic tissue distributions of the altered microsatellites revealed clues to their pathogenesis. The RER+ phenotype was homogeneously present in the primary tumors and their metastases and was absent from adjacent normal and hyperplastic endometrium. The altered microsatellites were predominantly the same sizes throughout five tumors but demonstrated greater intratumor heterogeneity in three tumors. In one case, the primary tumor was stable but its metastasis was unstable. Mutant c-K-ras alleles were significantly more frequent in RER+ (56%) than in RER negative (RER-) (14%) tumors (P = .0165) and appeared to be acquired after the RER+ phenotype in one tumor. There were no significant clinical differences between the RER+ and RER- tumors.

CONCLUSIONS AND IMPLICATIONS: The RER+ phenotype is frequently present in sporadic endometrial cancers and is expressed before and during clonal expansion. The underlying mutator mutations are probably heterogeneous, since the RER+ phenotypes were diverse. The absence of altered microsatellites in adjacent normal endometrium demonstrates that the expression of the RER+ phenotype is limited to neoplastic tissue. The bulk of the microsatellite alterations appeared to be acquired prior to clonal expansion, suggesting that expression of the underlying genomic instability contributes to, and is not a consequence of, transformation.

Author List

Duggan BD, Felix JC, Muderspach LI, Tourgeman D, Zheng J, Shibata D

Author

Juan Felix MD Vice Chair, Director, Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Autoradiography
Carcinoma
DNA Replication
DNA, Neoplasm
DNA, Satellite
Endometrial Neoplasms
Female
Genes, ras
Humans
Middle Aged
Mutation
Phenotype