title: Genomic instability and copy-number heterogeneity of chromosome 19q, including the kallikrein locus, in ovarian carcinomas.
abstract: Many tissue kallikrein (KLK) genes and proteins are candidate diagnostic, prognostic and predictive biomarkers for ovarian cancer (OCa). We previously demonstrated that the KLK locus (19q13.3/4) is subject to copy-number gains and structural rearrangements in a pilot study of cell lines and ovarian cancer primary tissues, shown to overexpress KLK gene family members. To determine the overall frequency of genomic instability and copy-number changes, a retrospective study was conducted using formalin-fixed paraffin embedded (FFPE) tissues. Eighty-one chemotherapy naïve serous OCas were examined using 3-colour fluorescence in situ hybridization (FISH) to identify structural and numerical changes on 19q, including the KLK locus; in addition to immunohistochemistry (IHC) for KLK6, which has been shown to be overexpressed in OCa. The KLK locus was subject to copy-number changes in ∼83% of cases: net gain in 51%, net loss in 30% and amplified in 2%; and found to be chromosomally unstable (p < 0.001). All cases showed a wide range of immuoreactivity for KLK6 by IHC. Although no strong correlation could be found with copy-number, the latter was contributing factor to the observed KLK6 protein overexpression. Moreover, univariate and multivariate analyses showed an association between the net loss of the KLK locus and longer disease-free survival. Interestingly, FISH analyses indicated that chromosome 19q was subjected to structural rearrangement in 62% of cases and was significantly correlated to tumor grade (p < 0.001). We conclude that numerical and structural aberrations of chromosome 19q, affect genes including the KLK gene members, may contribute to ovarian carcinoma progression and aggressiveness.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. jane.bayani@utoronto.ca
authors.forename: Jane
authors.initials: J
authors.lastname: Bayani
authors.forename: Paula
authors.initials: P
authors.lastname: Marrano
authors.forename: Cassandra
authors.initials: C
authors.lastname: Graham
authors.forename: Yingye
authors.initials: Y
authors.lastname: Zheng
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Katsaros
authors.forename: Heini
authors.initials: H
authors.lastname: Lassus
authors.forename: Ralf
authors.initials: R
authors.lastname: Butzow
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Diamandis
mesh_terms: D002888:Chromosomes, Human, Pair 19; D005260:Female; D018628:Gene Dosage; D018740:Genetic Heterogeneity; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D007610:Kallikreins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*
chemical_list: D007610:Kallikreins
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