In vivo differentiation and genomic evolution in adult male germ cell tumors

Abstract

Germ cell tumors (GCTs) are the most common solid malignancy in young adult men, but the genes and genomic regions involved in their etiology are not fully defined. We report here an investigation of DNA copy number changes in GCTs using 1 Mb BAC arrays. As expected, 12p gain was the defining genomic alteration, occurring in 72/74 GCTs. Parallel expression profiling of these tumors identified potential oncogenes from gained regions (LYN and RAB25) and potential tumor suppressor genes in regions of loss (SYNPO2, TTC12, IGSF4, and EPB41L3). Notably, we observed specific genomic alterations associated with histology, including gain of 17p11.2-q21.32 and loss of 2p25.3 in embryonal carcinoma, gain of 8p23.3-12 and loss of 5p15. 33-35.3, 11q23.1-25, and 13q12.11-34 in seminoma, and gain of 1q31.3-42.3, 3p, 14q11.2-32.33, and 20q and loss of 8q11.1-23.1 in yolk sac tumors (YST). Many significant genes that mapped to these regions had previously been associated with specific histologies, such as EOMES (chr3) and BMP2 (chr20) in YST and SPRY2 (chr13) and SOX17 (chr8) in seminomas. Additionally, our results suggest a model in which histologic differentiation of GCTs may drive genomic evolution. V V C 2007 Wiley-Liss, Inc.

Overexpressed oncogenic tumor-self antigens

“…TPD52 overexpression has been demonstrated in several human malignancies including breast, [76][77][78] prostate, [79][80][81] and ovarian carcinomas. 82 Expression microarray and other analyses predict TPD52 overexpression in many other cancers including multiple myeloma, 83,84 Burkitt's lymphoma, 85,86 pancreatic cancer, 87 testicular germ cell tumors, [88][89][90] and melanomas, 91,92 as well as multiple other adult and pediatric cancers. 93 Murine ortholog of TPD52 The murine ortholog of TPD52 (mD52) parallels normal tissue expression patterns and known functions of human TPD52 (hD52), with 86% amino acid identity.…”

Inhibition of the aurora kinases suppresses in vitro NT2-D1 cell growth and tumorigenicity

“…These findings have led to their evaluation as a potential target for anticancer therapy (Harrington et al 2004, Hata et al 2005, Matthew et al 2006, Manfredi et al 2007, Arlot-Bonnemains et al 2008, Mountzios et al 2008. TGCTs are characterized, as other types of solid tumors, by aneuploidy, and show an altered expression pattern of the aurora kinases (Oosterhuis et al 1989, Roelofs et al 2000, Chieffi et al 2004, Korkola et al 2008, Baldini et al 2010. This evidence identified the aurora kinases as new potential molecular targets also for the treatment of TGCT, especially against the most aggressive forms resistant to the conventional cisplatin-based chemotherapy (Nichols et al 1994, Horwich et al 2006, Fenner et al 2008.…”

“…More recently, we demonstrated, by means of quantitative RT-PCR and western blot analysis, that the expression of all three aurora kinases is deregulated in TGCT (Baldini et al 2010). Moreover, the chromosome region where the Aurora-C gene maps (19q13.43) is among the chromosomal regions that are most frequently lost in TGCT (Korkola et al 2008). These findings may have potential therapeutic implications.…”

Comparison of Clinical Subgroup aCGH Profiles through Pseudolikelihood Ratio Tests

“…To check sensitivity to threshold choice in instability assessment, values of 0.20 and 0.30 were also used in separate analyses. An additional analysis was conducted through use of the weighted median absolute deviation (MMAD) (see Korkola et al, 2008) in which a nonparametric estimate,σ, of the standard deviation for each hybridization is obtained using segmentation results. For this analysis, all clones belonging to segments with means above w = 2σ or below w = −2σ were categorized as gains or losses, respectively.…”

“…Segmentation was conducted through use of circular binary segmentation (CBS) (Olshen et al, 2004). Classification (i.e., assignment as loss, no-change, or gain) of the resultant segments was conducted through use of the weighted median absolute deviation (MMAD) as outlined by Korkola et al, 2008. Of note, the Willenbrock and Fridlyand approach is designed for the generation of aCGH data samples from a homogeneous population. The assessment of PLRT test power, however, requires comparisons between distinct subgroups.…”