TY - JOUR
T1 - Genomic and expression profiling of human spermatocytic seminomas
T2 - primary spermatocyte as tumorigenic precursor and DMRT1 as candidate chromosome 9 gene
AU - Looijenga, Leendert H J
AU - Hersmus, Remko
AU - Gillis, Ad J M
AU - Pfundt, Rolph
AU - Stoop, Hans J
AU - van Gurp, Ruud J H L M
AU - Veltman, Joris
AU - Beverloo, H Berna
AU - van Drunen, Ellen
AU - van Kessel, Ad Geurts
AU - Pera, Renee Reijo
AU - Schneider, Dominik T
AU - Summersgill, Brenda
AU - Shipley, Janet
AU - McIntyre, Alan
AU - van der Spek, Peter
AU - Schoenmakers, Eric
AU - Oosterhuis, J Wolter
PY - 2006/1/1
Y1 - 2006/1/1
N2 - Spermatocytic seminomas are solid tumors found solely in the testis of predominantly elderly individuals. We investigated these tumors using a genome-wide analysis for structural and numerical chromosomal changes through conventional karyotyping, spectral karyotyping, and array comparative genomic hybridization using a 32 K genomic tiling-path resolution BAC platform (confirmed by in situ hybridization). Our panel of five spermatocytic seminomas showed a specific pattern of chromosomal imbalances, mainly numerical in nature (range, 3-24 per tumor). Gain of chromosome 9 was the only consistent anomaly, which in one case also involved amplification of the 9p21.3-pter region. Parallel chromosome level expression profiling as well as microarray expression analyses (Affymetrix U133 plus 2.0) was also done. Unsupervised cluster analysis showed that a profile containing transcriptional data on 373 genes (difference of > or = 3.0-fold) is suitable for distinguishing these tumors from seminomas/dysgerminomas. The diagnostic markers SSX2-4 and POU5F1 (OCT3/OCT4), previously identified by us, were among the top discriminatory genes, thereby validating the experimental set-up. In addition, novel discriminatory markers suitable for diagnostic purposes were identified, including Deleted in Azospermia (DAZ). Although the seminomas/dysgerminomas were characterized by expression of stem cell-specific genes (e.g., POU5F1, PROM1/CD133, and ZFP42), spermatocytic seminomas expressed multiple cancer testis antigens, including TSP50 and CTCFL (BORIS), as well as genes known to be expressed specifically during prophase meiosis I (TCFL5, CLGN, and LDHc). This is consistent with different cells of origin, the primordial germ cell and primary spermatocyte, respectively. Based on the region of amplification defined on 9p and the associated expression plus confirmatory immunohistochemistry, DMRT1 (a male-specific transcriptional regulator) was identified as a likely candidate gene for involvement in the development of spermatocytic seminomas.
AB - Spermatocytic seminomas are solid tumors found solely in the testis of predominantly elderly individuals. We investigated these tumors using a genome-wide analysis for structural and numerical chromosomal changes through conventional karyotyping, spectral karyotyping, and array comparative genomic hybridization using a 32 K genomic tiling-path resolution BAC platform (confirmed by in situ hybridization). Our panel of five spermatocytic seminomas showed a specific pattern of chromosomal imbalances, mainly numerical in nature (range, 3-24 per tumor). Gain of chromosome 9 was the only consistent anomaly, which in one case also involved amplification of the 9p21.3-pter region. Parallel chromosome level expression profiling as well as microarray expression analyses (Affymetrix U133 plus 2.0) was also done. Unsupervised cluster analysis showed that a profile containing transcriptional data on 373 genes (difference of > or = 3.0-fold) is suitable for distinguishing these tumors from seminomas/dysgerminomas. The diagnostic markers SSX2-4 and POU5F1 (OCT3/OCT4), previously identified by us, were among the top discriminatory genes, thereby validating the experimental set-up. In addition, novel discriminatory markers suitable for diagnostic purposes were identified, including Deleted in Azospermia (DAZ). Although the seminomas/dysgerminomas were characterized by expression of stem cell-specific genes (e.g., POU5F1, PROM1/CD133, and ZFP42), spermatocytic seminomas expressed multiple cancer testis antigens, including TSP50 and CTCFL (BORIS), as well as genes known to be expressed specifically during prophase meiosis I (TCFL5, CLGN, and LDHc). This is consistent with different cells of origin, the primordial germ cell and primary spermatocyte, respectively. Based on the region of amplification defined on 9p and the associated expression plus confirmatory immunohistochemistry, DMRT1 (a male-specific transcriptional regulator) was identified as a likely candidate gene for involvement in the development of spermatocytic seminomas.
KW - Biomarkers, Tumor/biosynthesis
KW - Chromosomes, Human, Pair 9/genetics
KW - Female
KW - Gene Expression Profiling
KW - Genomic Instability
KW - Humans
KW - Immunohistochemistry
KW - Male
KW - Ovarian Neoplasms/genetics
KW - Seminoma/genetics
KW - Spermatocytes/pathology
KW - Testicular Neoplasms/genetics
KW - Transcription Factors/genetics
UR - http://www.scopus.com/inward/record.url?scp=31544473100&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-05-2936
DO - 10.1158/0008-5472.CAN-05-2936
M3 - Article
C2 - 16397242
SN - 0008-5472
VL - 66
SP - 290
EP - 302
JO - Cancer research
JF - Cancer research
IS - 1
ER -