title: Minimum regions of genomic imbalance in stage I testicular embryonal carcinoma and association of 22q loss with relapse.
abstract: Testicular germ cell tumors (TGCT) are the most frequent solid tumor to affect young adult males and are histologically divided into seminomas and nonseminomas (NS). NS comprise undifferentiated embryonal carcinoma (EC) and differentiated tumors with embryonic (teratoma) or extra-embryonic (choriocarcinoma, yolk sac tumor) features. In contrast to other subtypes, EC have uniform cellular morphology and lack normal cell infiltrates, ideal for nucleic acid profiling. EC are under-represented in previous studies due to their relative rarity. To gain insights into NS tumorigenesis, metastatic dissemination and potential markers of relapse, a full tiling path BAC platform was used to obtain array comparative genomic hybridization (aCGH) profiles from 32 formalin fixed paraffin embedded stage I EC samples from patients with follow-up data. In addition to identifying regions previously described in TGCT, novel minimum overlapping regions of gain at 6p21.33, 10q11.21, and 22q13.32 and loss at 22q12.2 were defined and confirmed by fluorescence in situ hybridization analyses. Specifically, the region at 6p21.33 included OCT3/4, the expression of which is involved in the maintenance of pluripotency and the 10q11.21 region contains the gene encoding the RAS activating factor RASGEF1A, the expression of which was demonstrably increased in RNA extracted from these samples. The region of loss at 22q12.2 was more frequently seen in tumors that relapsed and protein expression of genes from 22q12.2 included PIK3IP1, a negative regulator of PI3 kinase signaling was reduced. These data support the role for genes involved in pluripotency and RAS/PI3K signaling in EC development and progression.
authors.affiliation: Molecular Cytogenetics, Section of Molecular Carcinogenesis, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Gilbert
authors.forename: Alan
authors.initials: A
authors.lastname: McIntyre
authors.forename: Brenda
authors.initials: B
authors.lastname: Summersgill
authors.forename: Edoardo
authors.initials: E
authors.lastname: Missiaglia
authors.forename: Neil C
authors.initials: NC
authors.lastname: Goddard
authors.forename: Ian
authors.initials: I
authors.lastname: Chandler
authors.forename: Robert A
authors.initials: RA
authors.lastname: Huddart
authors.forename: Janet
authors.initials: J
authors.lastname: Shipley
mesh_terms: D000328:Adult; D022981:Allelic Imbalance / Q000235:genetics; D018236:Carcinoma, Embryonal / Q000235:genetics* / Q000473:pathology*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D012008:Recurrence; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C521076:PIK3IP1 protein, human; C516782:RASGEF1A protein, human; D020663:ras Guanine Nucleotide Exchange Factors; C078418:developmentally regulated GTP-binding protein; D019204:GTP-Binding Proteins