Amplification of the 20q Chromosomal Arm Occurs Early in Tumorigenic Transformation and May Initiate Cancer

Abstract

Duplication of chromosomal arm 20q occurs in prostate, cervical, colon, gastric, bladder, melanoma, pancreas and breast cancer, suggesting that 20q amplification may play a causal role in tumorigenesis. According to an alternative view, chromosomal imbalance is mainly a common side effect of cancer progression. To test whether a specific genomic aberration might serve as a cancer initiating event, we established an in vitro system that models the evolutionary process of early stages of prostate tumor formation; normal prostate cells were immortalized by the over-expression of human telomerase catalytic subunit hTERT, and cultured for 650 days till several transformation hallmarks were observed. Gene expression patterns were measured and chromosomal aberrations were monitored by spectral karyotype analysis at different times. Several chromosomal aberrations, in particular duplication of chromosomal arm 20q, occurred early in the process and were fixed in the cell populations, while other aberrations became extinct shortly after their appearance. A wide range of bioinformatic tools, applied to our data and to data from several cancer databases, revealed that spontaneous 20q amplification can promote cancer initiation. Our computational model suggests that 20q amplification induced deregulation of several specific cancer-related pathways including the MAPK pathway, the p53 pathway and Polycomb group factors. In addition, activation of Myc, AML, B-Catenin and the ETS family transcription factors was identified as an important step in cancer development driven by 20q amplification. Finally we identified 13 "cancer initiating genes", located on 20q13, which were significantly over-expressed in many tumors, with expression levels correlated with tumor grade and outcome suggesting that these genes induce the malignant process upon 20q amplification.

PTP1B Is an Androgen Receptor–Regulated Phosphatase That Promotes the Progression of Prostate Cancer

“…4F) and nuclear localization (Fig 4D). All together, these results clearly establish PTPN1 as an AR-regulated gene, and corroborate findings of a previous study that reported the co-amplification of PTPN1 and AR in a human prostate cancer xenograft model (39, 40). Interestingly, PTPN1 is located on chromosome 20q13, a region frequently amplified in several tumor types (40).…”

“…All together, these results clearly establish PTPN1 as an AR-regulated gene, and corroborate findings of a previous study that reported the co-amplification of PTPN1 and AR in a human prostate cancer xenograft model (39, 40). Interestingly, PTPN1 is located on chromosome 20q13, a region frequently amplified in several tumor types (40). Despite conflicting results that question the relevance of this amplified region in hereditary prostate cancer (41), the fact that PTPN1 is frequently amplified in metastatic tumors as well as in a subset of high-risk primary tumors (Fig.…”

The New Immortalized Uroepithelial Cell Line HBLAK Contains Defined Genetic Aberrations Typical of Early Stage Urothelial Tumors

“…Whereas high level amplifications correlated with tumor progression in breast cancer [37], low-level amplifications appeared to be rather associated with early stage ovarian carcinoma [38]. Similarly, 20q gain also occurred as an early event in normal prostatic cells immortalized by TERT overexpression, where a number of oncogenes in the 20q13.2 region cooperate to support immortalization [39]. Gains at 20q thus appear to represent an early event in the evolution of a  malignant phenotype [39].…”

Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia

“…The AURKA gene is located in chromosome arm 20q, which is often amplified in many human cancers and contains multiple oncogenes 49 . We examined AURKA amplification in HNSCCs, but this was not associated with the intensity of AURKA staining ( Supplementary Fig.…”