Abstract 1177: Genomic abnormality and genetic alterations of a novel ZMIZ1 gene at human chromosome 10q22.3 in oncogenesis and prognosis

Abstract

Abstract Chromosomal abnormalities and genomic instability in 10q22.3 region have been associated with lung cancer development, histopathological staging, and poor prognosis. Genetic mapping identified several genes including ZMIZ1, SFTPA1 and SFTPA2 in this critical region. Loss, interruption or gain of function of these genes in association with 10q22.3 deletions, translocations, or amplifications that were frequently detected in human primary lung cancer and cancer cell lines may promote oncogenesis. Human ZMIZ1, also named hZimp10, is a novel PIAS (protein inhibitor of activated STAT)-like protein that shares a zing finger domain, MIZ (MSX-interacting zinc finger), with other PIAS proteins. Fusion of ZMIZ1 to ABL1 with a t(9;10)(q34;q22.3) translocation was identified in a B-cell acute lymphoblastic leukemia patient. In this study, we performed fluorescence in situ hybridization (FISH) using genomic DNA probes covering ZMIZ1 and SFTPA gene loci at 10q22.3 to determine chromosomal aberrations involving the ZMIZ1 gene in primary lung tumor samples and lung cancer cell lines. Chromosomal abnormalities at 10q22.3 loci, including deletions, polysomy, and translocations were frequently detected in tumors and tumor-derived cell lines. We analyzed copy number variations specifically linked to ZMIZ1 gene loci by mining the published genome-wide SNP dataset from 370 NSCLC tumor samples and confirmed a significant copy number gain with average copy numbers (CN) > 5 or loss with CN < 1.5, respectively. A high frequency of loss of heterozygosity (LOH) of ZMIZ1 and ABL1 genes in lung cancer cell lines and high level amplifications of ZMIZI gene (CN > 7) in breast and prostate cancer cell lines were also detected in Sanger SNP and CGP databases, respectively. We performed Spectral karyotyping (SKY) analysis to identify chromosomal abnormalities and potential translocations involved in the 10q region in lung cancer cell lines. We found that the 10q region was translocated and fused with other chromosomes extensively in H1819 cells. This result was consistent with the high frequency 10q chromosomal abnormalities detected in human lung and other cancer cell lines in the NCI/NCBI SKY/M-FISH & CGH database. Furthermore, we developed and performed a high-throughput RACE-PCR-based gene-specific RNA sequencing analysis using next-generation parallel sequencing technology (454 Life Sciences, Inc.) to search for potential transcriptional variants and fusion partners of the ZMIZ1 gene in lung cancer cell lines which has revealed potential fusion mRNA. These results suggest that ZMIZ1 may play an important role in lung cancer development and serve as a useful biomarker for lung cancer molecular staging and prognosis. (Supported by NIH/NCI grants SPORE P50CA70907 and RO1CA116322) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1177.