title: Loss of heterozygosity proximal to the M6P/IGF2R locus is predictive for the presence of disseminated tumor cells in the bone marrow of ovarian cancer patients before and after chemotherapy.
abstract: Disseminated tumor cells (DTC) in the bone marrow (BM) are present in about 35% of ovarian cancers before surgery and after chemotherapy and are associated with worse prognosis. A molecular biomarker in the primary tumor predicting tumor cell spread would be highly desirable. The purpose of the study was to investigate loss of heterozygosity (LOH) in primary ovarian tumors at four ovarian cancer-relevant chromosomal loci involved in apoptosis, platinum sensitivity, or DNA-repair, to assess the prognostic value of LOH and to correlate LOH with DTC occurrence before surgery and after chemotherapy. Primary tumor DNA of 88 patients was analyzed for LOH at four polymorphic microsatellite markers using PCR-based fluorescence microsatellite analysis. BM aspirates were analyzed for DTC by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. LOH at the entire marker set correlated with tumor grading (P = 0.0001) and histology (P = 0.004). LOH at marker D10S1765 correlated with FIGO stage (P = 0.046) and grading (P = 0.05), whereas LOH at D17S855 significantly associated with grading (P = 0.023) and histology (P = 0.012), respectively. DTC were detected in 49% of patients before surgery and in 50% of patients after chemotherapy. Interestingly, LOH proximal to D6S1581 significantly correlated with DTC presence before surgery (P = 0.05) and after chemotherapy (P = 0.022). Conclusively, our data suggest that allelic loss at D6S1581 (proximal to M6P/IGF2R locus) serves as a molecular biomarker for the presence of DTC in the BM before and after chemotherapy.
authors.affiliation: Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jan Dominik
authors.initials: JD
authors.lastname: Kuhlmann
authors.forename: Heidi
authors.initials: H
authors.lastname: Schwarzenbach
authors.forename: Friedrich
authors.initials: F
authors.lastname: Otterbach
authors.forename: Martin
authors.initials: M
authors.lastname: Heubner
authors.forename: Pauline
authors.initials: P
authors.lastname: Wimberger
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Worm
authors.forename: Rainer
authors.initials: R
authors.lastname: Kimmig
authors.forename: Sabine
authors.initials: S
authors.lastname: Kasimir-Bauer
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D001853:Bone Marrow / Q000473:pathology*; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011379:Prognosis; D017527:Receptor, IGF Type 2 / Q000235:genetics*; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; D017527:Receptor, IGF Type 2; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human