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Genotypic and phenotypic progression in endometrial tumorigenesis: determining when defects in DNA mismatch repair and KRAS2 occur. Genes Chromosomes Cancer 2001 Dec;32(4):295-301

Date

12/18/2001

Pubmed ID

11746970

DOI

10.1002/gcc.1194

Scopus ID

2-s2.0-0035164146 (requires institutional sign-in at Scopus site)   17 Citations

Abstract

We set out to determine the relative timing of loss of DNA mismatch repair and KRAS2 mutation in endometrial tumorigenesis. We studied endometrial carcinoma (CA) and synchronous atypical endometrial hyperplasia (AEH), the premalignant precursor of endometrial cancer. Carcinoma and hyperplasia were investigated for loss of mismatch repair as evidenced by microsatellite instability (MSI) and for KRAS2 mutations. Endometrial cancers previously shown to be MSI-positive were evaluated for KRAS2 codon 12 and 13 mutations. DNA was isolated from foci of AEH concomitant with, but physically remote from, the cancers by use of tissues prepared by laser capture microdissection (LCM). The AEH DNAs were then assessed for MSI and KRAS2 mutations. Of 210 endometrial CAs investigated, 51 (26%) were MSI-positive, and among those, 21 (41%) arose concomitantly with AEH. Of 41 foci of AEH (mean, two foci per patient) investigated, 34 (83%) were MSI-positive. KRAS2 mutations were seen in 5/51 (10%) MSI-positive carcinomas. From the five patients informative for both KRAS2 mutation and MSI, 10 foci of AEH were available for investigation. All 10 AEH specimens (100%) were MSI-positive, and six (60%) had the KRAS2 mutation present in the coexisting CA. The observation that some MSI-positive AEH specimens lack the KRAS2 mutation seen in the coexisting CA supports a model in which loss of DNA mismatch repair precedes KRAS2 mutation. However, in addition to the absence of KRAS2 mutations in AEH, we discovered mutations in LCM hyperplasia and carcinoma specimens that were not present in the portion of the cancers originally investigated. These discordant genotypes suggest genetic heterogeneity in endometrial hyperplasia and concomitant cancer.

Author List

Cohn DE, Mutch DG, Herzog TJ, Rader JS, Dintzis SM, Gersell DJ, Todd CR, Goodfellow PJ

Author

Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin




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

Base Pair Mismatch
Carcinoma
DNA Repair
Disease Progression
Endometrial Hyperplasia
Endometrial Neoplasms
Female
Genotype
Humans
Mutation
Phenotype
Proto-Oncogene Proteins
Proto-Oncogene Proteins p21(ras)
ras Proteins