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Human testicular germ cell tumour (TGCT) of adolescents and young adults develop from precursor lesions called carcinoma in situ (CIS), which is believed to originate from diploid primordial germ cells during foetal life. CIS is initiated by an aneuploidisation event accompanied by extensive chromosome instability. The further transformation of CIS into invasive TGCT (seminomas and nonseminomas) is associated with increased copy number of chromosome arm 12p, most often seen as isochromosome 12p. Despite the morphological distinctions between seminomatous and nonseminomatous TGCTs, they have many of the same regional genomic disruptions, although frequencies may vary. However, the two histological subtypes have quite distinct epigenomes, which is further evident from their different gene expression patterns. CIS develops from cells with erased parental imprinting, and the seminoma genome is under-methylated compared to that of the nonseminoma genome. High throughput microarray technologies have already pinpointed several genes important to TGCT, and will further unravel secrets of how specific genes and pathways are regulated and deregulated throughout the different stages of TGCT tumourigenesis. In addition to acquiring new insights into the molecular mechanisms of TGCT development, understanding the TGCT genome will also provide clues to the genetics of human embryonic development and of chemotherapy response, as TGCT is a good model system to both.

We have shown recently that about half of the human TGCTs(3) reveal DNA copy number increases affecting two distinct regions on chromosome arm 17q. To identify potential target genes with elevated expressions attributable to the extra copies, we constructed a cDNA microarray containing 636 genes and expressed sequence tags from chromosome 17. The expression patterns of 14 TGCTs, 1 carcinoma in situ, and 3 normal testis samples were examined, all with known chromosome 17 copy numbers. The growth factor receptor-bound protein 7 (GRB7) and junction plakoglobin (JUP) were the two most highly overexpressed genes in the TGCTs. GRB7 is tightly linked to ERBB2 and is coamplified and coexpressed with this gene in several cancer types. Interestingly, the expression levels of ERBB2 were not elevated in the TGCTs, suggesting that GRB7 might be the target for the increased DNA copy number in TGCTs. Because of the limited knowledge of altered gene expression in the development of TGCTs, we also examined the expression levels of 512 additional genes located throughout the genome. Several genes novel to testicular tumorigenesis were consistently up- or down-regulated, including POV1, MYCL1, MYBL2, MXI1, and DNMT2. Additionally, overexpression of the proto-oncogenes CCND2 and MYCN were confirmed from the literature. The overexpressions were for some of the target genes closely associated to either seminoma or nonseminoma TGCTs, and hierarchical cluster analysis of the gene expression data effectively distinguished among the known histological subtypes. In summary, this focused functional genomic characterization of TGCTs has lead to the identification of new gene targets associated with a common genomic rearrangement as well as other genes with potential importance to testicular tumorigenesis.