Abstract 807: Eight candidate target genes of the recurrent 3p12-p14 loss in cervical cancer.

Genetic gains and losses, i.e. gene dosage alterations, influence gene expressions and thereby promote tumor development and progression. Identification and functional assessment of such alterations may help to understand the biology of the disease and be useful for the discovery of diagnostic and therapeutic biomarkers. The recurrent 3p12-p14 loss in cervical cancer has been proposed as a prognostic biomarker, however, its pathogenetic role, including its target genes, remains to be clarified. The purpose of this work was to identify 3p target genes in cervical cancer, and explore their role in the development of chemoradioresistance. Cox regression analysis of the 3p gene dosages showed that loss of 3p11.2-p14.2 was significantly associated with clinical outcome. To depict candidate target genes of the loss, pairwise gene dosage and expression profiling was performed on 77 patients by array comparative genomic hybridization and Illumina gene expression beadarrays, respectively, including all genes within the 3p11.2–p14.2 region. The expression of eight of the 147 genes within the region; i.e., THOC7, PSMD6, SLC25A26, TMF1, RYBP, SHQ1, EBLN2, and GBE1, were highly downregulated in cases with loss. This was confirmed at the protein level for RYBP and TMF1 in 150 patients by immunohistochemistry. A gene signature with the expression values of the eight candidate genes was constructed to explore the prognostic impact of all genes combined. Unsupervised hierarchical clustering divided the patients into two groups, for which the group with downregulation of the genes had the highest frequency of 3p loss and a poor outcome compared to the other. A 3p target gene score was calculated for each tumor, and was shown to be lower for patients with 3p loss and associated with clinical outcome. The prognostic impact of the eight gene signature was confirmed in a validation cohort of 74 patients, showing a worse outcome for patients with a low 3p target gene score, confirming the clinical significance of the signature. To assess the importance of the signature in comparison to existing clinical markers, we merged the two cohorts to a group of 151 patients. In univariate Cox regression analysis, the 3p target gene score was associated with outcome. All eight genes showed a significant or clear tendency towards a relationship to outcome in a single gene analysis, and therefore seemed to contribute to the univariate result. In multivariate analysis, the score emerged as a prognostic factor independent of lymph node status, tumor size, and stage. These results support a role of the eight candidate genes as targets of the 3p12–p14 loss in cervical cancer and propose their use as biomarker in the clinical decision-making. Citation Format: Malin Lando, Marit Holden, Ruth Holm, Gunnar B. Kristensen, Heidi Lyng. Eight candidate target genes of the recurrent 3p12-p14 loss in cervical cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 807. doi:10.1158/1538-7445.AM2013-807