Amplification of CyclinL1 in uterine cervical carcinoma has prognostic implications

Abstract

The chromosomal 3q25.31 region was consistently amplified in primary cancer of cervix (CACX). CyclinL1 is a candidate gene of this region and already have been implicated as an oncogene in head and neck cancers. In this study, we aimed to investigate the involvement of CyclinL1 in cervical carcinogenesis and for this purpose its copy number variation (CNV) was studied in 23 cervical intraepithelial neoplasia (CIN) and 110 CACX samples. In CIN lesions CyclinL1 was not amplified; however, the amplification frequency was 16% (9/56) in stage I/II tumors which remained comparable during subsequent stages of tumorigenesis. This implied association of CyclinL1 amplification with development of early invasiveness. Quantitation of mRNA expression revealed 2.6 ± 1.53-fold overexpression of this gene in primary CACX. The amplification/copy number gain of CyclinL1 and its mRNA profile were concordant, in tumors. Immunohistochemical (IHC) analysis in primary CACX, cell lines: SiHa and HeLa revealed intense nuclear expression of cyclinL1, which was further confirmed by Western blot in the cell lines. However 47% (7/15) CACX samples expressed high/intermediate level of cyclin L1. Kaplan–Meier survival analysis indicated CyclinL1 amplification as a determinant of poor patient outcome. Tumor radio-resistance developed as a consequence of CyclinL1 amplification. Cox multivariate analysis revealed that multiparous (≥5) CACX patients with amplified CyclinL1 locus along with advanced tumor stage (III/IV) had worst prognosis. Our data suggest importance of CyclinL1 in cervical carcinogenesis with its associated pathways viz: pre-mRNA splicing, cell-cycle regulation (G₀/G₁ and G₂/M) being potential targets of therapeutic interventions in CACX.