Increased copy number of imprinted genes in the chromosomal region 20q11-q13.32 is associated with resistance to antitumor agents in cancer cell lines

Abstract

Background Parent of origin-specific allelic expression of imprinted genes is epigenetically controlled. In cancer, imprinted genes undergo both genomic and epigenomic alterations, including frequent copy number changes. We investigated whether copy number loss or gain of imprinted genes in cancer cell lines is associated with response to chemotherapy treatment. Results We analyzed 198 human imprinted genes including protein-coding genes and noncoding RNA genes using data from tumor cell lines from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We examined whether copy number of the imprinted genes in 35 different genome locations was associated with response to cancer drug treatment. We also analyzed associations of pretreatment expression and DNA methylation of imprinted genes with drug response. Higher copy number of BLCAP, GNAS, NNAT, GNAS-AS1, HM13, MIR296, MIR298, and PSIMCT-1 in the chromosomal region 20q11-q13.32 was associated with resistance to multiple antitumor agents. Increased expression of BLCAP and HM13 was also associated with drug resistance, whereas higher methylation of gene regions of BLCAP, NNAT, SGK2, and GNAS was associated with drug sensitivity. While expression and methylation of imprinted genes in several other chromosomal regions was also associated with drug response and many imprinted genes in different chromosomal locations showed a considerable copy number variation, only imprinted genes at 20q11-q13.32 had a consistent association of their copy number with drug response. Copy number values among the imprinted genes in the 20q11-q13.32 region were strongly correlated. They were also correlated with the copy number of cancer-related non-imprinted genes MYBL2, AURKA, and ZNF217 in that chromosomal region. Expression of genes at 20q11-q13.32 was associated with ex vivo drug response in primary tumor samples from the Beat AML 1.0 acute myeloid leukemia patient cohort. Association of the increased copy number of the 20q11-q13.32 region with drug resistance may be complex and could involve multiple genes. Conclusions Copy number of imprinted and non-imprinted genes in the chromosomal region 20q11-q13.32 was associated with cancer drug resistance. The genes in this chromosomal region may have a modulating effect on tumor response to chemotherapy.

Construction of circRNA-miRNA-mRNA Network Involved in Pituitary Adenoma using High-Throughput Sequencing and Bioinformatics Analysis

“…NRXN3 was shown to be associated with tumor aggressiveness in studies of gliomas and glioblastoma patients with high NRXN3 expression were found to have a poor prognosis [39] . By analyzing the Cancer Cell Line Encyclopedia (CCLE)-Genomics of Drug Sensitivity in Cancer (GDSC) dataset, Krushkal et al found a significant correlation between increased GNAS expression and tumor resistance to chemotherapeutic agents [40] . Furthermore, GNAS activation significantly promoted growth and progression in a mouse model of Small Cell Lung Cancer (SCLC) [41] .…”