title: DNA mismatch repair and TP53 defects are early events in uterine carcinosarcoma tumorigenesis.
abstract: Growing molecular evidence shows that uterine carcinosarcomas are clonal tumors. The carcinoma component has a dominant effect in the aggressive clinical behavior of these tumors. Defective DNA mismatch repair affects up to 30% of endometrial adenocarcinomas. The frequency and importance of defective DNA mismatch repair in the histiogenesis of uterine carcinosarcomas remains controversial. We studied the pattern and frequency of defective DNA mismatch repair and TP53 alterations in the epithelial and mesenchymal components of 28 uterine carcinosarcomas. We found evidence of defective DNA mismatch repair in six cases (21%) with a concordance rate of 83% for carcinoma-sarcoma pairs (kappa=0.887, P<0.001). Lack of immunostaining for the MLH1 protein was demonstrated in both components in two of these tumors. TP53 defects were evaluated by 17p deletion analysis and p53 immunostaining. Nineteen carcinoma (68%) and 18 sarcoma (64%) components had evidence of either TP53 allelic loss or p53 overexpression. These defects proved clonal in 76% of cases (kappa=0.602, P=0.003). Our results indicate that defective DNA mismatch repair and TP53 defects are common early events in carcinosarcoma tumorigenesis. The high rate of concordance for these molecular defects between the carcinoma and sarcoma components adds to existing molecular evidence that carcinosarcomas are clonal malignancies.
authors.affiliation: Division of Gynecologic Oncology, Washington University School of Medicine and Siteman Cancer Center, St Louis, MO 63110, USA. taylorni@msnotes.wustl.edu
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Taylor
authors.forename: Israel
authors.initials: I
authors.lastname: Zighelboim
authors.forename: Phyllis C
authors.initials: PC
authors.lastname: Huettner
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Powell
authors.forename: Randall K
authors.initials: RK
authors.lastname: Gibb
authors.forename: Janet S
authors.initials: JS
authors.lastname: Rader
authors.forename: David G
authors.initials: DG
authors.lastname: Mutch
authors.forename: Tina B
authors.initials: TB
authors.lastname: Edmonston
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D020137:Base Pair Mismatch; D002296:Carcinosarcoma / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000032:analysis; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D043171:Chromosomal Instability; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats / Q000235:genetics; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000032:analysis; D009687:Nuclear Proteins / Q000032:analysis; D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014594:Uterine Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein