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Genomic instability and copy-number heterogeneity of chromosome 19q, including the kallikrein locus, in ovarian carcinomas.

20800559

Mol Oncol. 2011 Feb 5 (1).

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.

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