Gene expression profiling differentiates germ cell tumors from other cancers and defines subtype-specific signatures

Abstract

Germ cell tumors (GCTs) of the testis are the predominant cancer among young men. We analyzed gene expression profiles of 50 GCTs of various subtypes, and we compared them with 443 other common malignant tumors of epithelial, mesenchymal, and lymphoid origins. Significant differences in gene expression were found among major histological subtypes of GCTs, and between them and other malignancies. We identified 511 genes, belonging to several critical functional groups such as cell cycle progression, cell proliferation, and apoptosis, to be significantly differentially expressed in GCTs compared with other tumor types. Sixty-five genes were sufficient for the construction of a GCT class predictor of high predictive accuracy (100% training set, 96% test set), which might be useful in the diagnosis of tumors of unknown primary origin. Previously described diagnostic and prognostic markers were found to be expressed by the appropriate GCT subtype (AFP, POU5F1, POV1, CCND2, and KIT). Several additional differentially expressed genes were identified in teratomas (EGR1 and MMP7), yolk sac tumors (PTPN13 and FN1), and seminomas (NR6A1, DPPA4, and IRX1). Dynamic computation of interaction networks and mapping to existing pathways knowledge databases revealed a potential role of EGR1 in p21-induced cell cycle arrest and intrinsic chemotherapy resistance of mature teratomas. testicular cancer ͉ unknown primary tumors ͉ DNA microarrays ͉ molecular interaction networks H uman germ cell tumors (GCTs) are a diverse group of neoplasms that most commonly arise in the gonads, particularly in the testis. They account for up to 60% of all malignancies diagnosed in men between 20 and 40 years of age. Their incidence (6-11 per 100,000) has increased among Caucasians in recent decades, with an annual increase of 3-6% (1).The histopathological classification of GCTs has been controversial because of the different concepts of histogenesis of these neoplasms, as well as the pluripotent nature of transformed primordial germ cells. GCTs can mimic normal patterns of embryonic segregation and differentiation, giving rise to structures resembling embryonic (endoderm, mesoderm, ectoderm) and extra-embryonic (yolk sac, trophoblast) derivatives. On the basis of the presence of those elements, they are further divided into pure GCTs (seminoma, embryonal carcinoma, teratoma, choriocarcinoma, and yolk sac tumor) or mixed GCTs, if more than one element is present.Compared with most cancers of adults, GCTs are highly sensitive to chemotherapy (2). Even with metastases, 80% of GCT patients can be cured by cisplatin-based combination chemotherapy, followed by secondary resection of residual tumor lesions, which can contain necrotic cells, viable malignant cells, or mature teratoma. In contrast to the other histological subtypes, mature teratomas show a less aggressive clinical behavior, but are unresponsive to chemotherapy. The biological bases for the chemosensitivity of GCTs and the clinical behavior of mature teratomas are unclear (3).In this study, ...

Expression profile of skin papillomas with high cancer risk displays a unique genetic signature that clusters with squamous cell carcinomas and predicts risk for malignant conversion

“…Microarray technology has been used to identify gene expression patterns associated with different stages of cancer, different cancer types and to generate predictors of therapeutic response (Glinsky et al, 2004;Lossos et al, 2004;Nambiar et al, 2004;Juric et al, 2005). In the mouse skin carcinogenesis model microarrays have identified genes whose expression is associated with tumor promotion, with benign and malignant stages of tumor progression or with malignant progression and metastasis (Dong et al, 1997;Serewko et al, 2002;Dooley et al, 2003;Hummerich et al, 2006;Ridd et al, 2006).…”

Diagnostic markers for germ cell neoplasms: from placental-like alkaline phosphatase to micro-RNAs

“…Likewise, pluripotent characteristics of GCT observed previously by pathologists, has been demonstrated by molecular studies, including numerous microarray studies, which detected in these tumours (excluding teratoma) as well as in human PGCs/gonocytes, a high expression of embryonic factors involved in pluripotency regulation, such as POU5F1(OCT4), NANOG, SOX2, REX1, UTF1 or LIN28 [38][39][40][41][42][43][44][45][46][47]. These studies have also identified differences between the GCT subtypes, e.g.…”

Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer

“…Interestingly, the cyclin-dependent kinase (CDK) inhibitor p21 cip1/waf1 (p21) has been shown to inhibit apoptosis (10)(11)(12)(13). Remarkably, several studies have demonstrated that p21 protein and CDKN1A mRNA expression are abundantly expressed in more differentiated TCs, such as mature teratoma (14,15). Worthy of note, these teratomas are resistant to cisplatin-based chemotherapy (8,(15)(16)(17).…”

“…Remarkably, several studies have demonstrated that p21 protein and CDKN1A mRNA expression are abundantly expressed in more differentiated TCs, such as mature teratoma (14,15). Worthy of note, these teratomas are resistant to cisplatin-based chemotherapy (8,(15)(16)(17). In contrast, p21 is almost not detectable in seminomas and embryonal carcinomas (EC) that are predominantly sensitive to cisplatin (9,14,18).…”