Expression profile of genes from 12p in testicular germ cell tumors of adolescents and adults associated with i(12p) and amplification at 12p11.2–p12.1

Abstract

Gain of 12p material is invariably associated with testicular germ cell tumors (TGCTs) of adolescents and adults, most usually as an isochromosome 12p. We analyzed TGCTs with i(12p) using a global approach to expression profiling targeting chromosomes (comparative expressed sequence hybridization, CESH). This indicated overexpression of genes from 12p11.2-p12.1 relative to testis tissue and fibroblasts. The nonseminoma subtype showed higher levels of expression than seminomas. Notably, 12p11.2-p12.1 is amplified in about 10% of TGCTs and CESH analysis of such amplicon cases showed high levels of overexpression from this region. Microarray analysis, including cDNA clones representing most UniGene clusters from 12p11.2-p12.1, was applied to DNA and RNA from 5 TGCTs with amplification of 12p11.2-p12.1 and seven TGCTs with gain of the entire short arm of chromosome 12. Expression profiles were consistent with the CESH data and overexpression of EST595078, MRPS35 and LDHB at 12p11.2-p12.1 was detected in most TGCTs. High-level overexpression of BCAT1 was specific to nonseminomas and overexpression of genes such as CMAS, EKI1, KRAS2, SURB7 and various ESTs correlated with their amplification. Genes such as CCND2, GLU3, LRP6 and HPH1 at 12p13 were also overexpressed. The overexpressed sequences identified, particularly those in the region amplified, represent candidate genes for involvement in TGCT development.

Genomic copy number and expression patterns in testicular germ cell tumours

“…These regions included known differences of 12p overexpression associated with TGCT (Rodriguez et al, 2003) and 9p21 associated with SSE (Looijenga et al, 2006). Novel differences included overexpression from 4q22 and 5q23.2 associated with SSE.…”

“…NS, which have a median age at diagnosis of 25, exhibit various stages of differentiation with cells from embryonic, extra-embryonic and somatic tissue types (Mostofi, 1973). Material from the short arm of chromosome 12 is invariably gained in these tumours and in roughly 10% of cases a smaller region of gain at 12p11.2 -p12.1 has been defined (Rodriguez et al, 2003;Zafarana et al, 2003).…”

“…In recent years, a number of expression profiling studies have been reported and these have identified overexpressed genes and expression signatures, which distinguish different subtypes of NS (Skotheim et al, 2005). Although we have previously examined gene copy number and expression changes associated with 12p (Rodriguez et al, 2003), few studies have integrated genomic and expression array data for the entire genome of TGCT (Skotheim et al, 2006). Factors predicted to influence gene expression include genomic copy number and epigenetic factors such as methylation.…”

Origins and molecular biology of testicular germ cell tumors

“…68 The consistent gain of 12p genetic material is supported by gene array and comparative genomic hybridization data. 69,70 The presence of i(12p) in IGCNU is a matter of controversy with most investigators suggesting it is not present. 2,14 This finding tends to support the Skakkebaek hypothesis that polyploidization is an initiating event followed by i(12p) in the invasive phenotype.…”

Genome-wide gene expression profiling of testicular carcinoma in situ progression into overt tumours

“…A range of studies has recently reported gene expression patterns in overt TGCT. Several studies have focused on genes on chromosomes 17 and 12, because of frequent rearrangements of these chromosomes Rodriguez et al, 2003;. One study reported gene expression patterns of testicular SEM compared to normal testicular parenchyma (Okada et al, 2003), and another study have reported gene expression in SEM-and embryonic carcinoma (EC)-derived cell lines (Sperger et al, 2003).…”