title: Genomic screening of testicular germ cell tumors from monozygotic twins.
abstract: BACKGROUND
  Testicular germ cell tumors (TGCTs) account for 1-2% of all tumors in young and middle aged men. A 75-fold increase in TCGT development has been reported for monozygotic (MZ) twins. Therefore, the occurrence of simultaneous tumors in MZ twins emphasizes the importance of genetic factors that influence the risk of developing these tumors. Genomic screening was performed for one family containing MZ twins with testicular germ cell tumors, in order to define alterations associated with risk of tumor development.
  
  
  METHODS
  Copy number alterations were evaluated using array-CGH (4x44K, Agilent Technologies) in one seminoma and one embryonal carcinoma (EC) from MZ twins. In addition, genomic alterations from the tumors and peripheral blood cells of the twins were compared to the parental genomes via their peripheral blood cells.
  
  
  RESULTS
  Embryonal carcinoma (Twin-1 t) presented a lower frequency of genomic alterations compared to the seminoma (Twin-2 t). One minimal common region of loss was observed in 9p13.1-p12 in the comparison between DNA from blood samples for Twin-1 and Twin-2. In this region is mapped the CNTNAP3 gene which was confirmed as involved in losses by qPCR. Comparative analysis of novel CNVs between the Twin-1 t and Twin-2 t showed five minimal common regions involving gain at chromosomes 12 (12p12.3-p11.1 and 12p13.33-p12.3), while losses were observed at 10p15.3-p15.2, 13q21.1-q21.2 and 15q11.1-q11.2. In addition, one exclusive rare copy number alteration was detected in Twin-1 t and Twin-2 t, and 19 novel alterations were identified in the Twin-2 t.
  
  
  CONCLUSIONS
  Distinct genomic profiles for MZ twins with phenotypically different TGCT were described. Of particular interest, 12p gains were detected exclusively in tumor samples. In peripheral blood samples, loss of 9p13.1-p12 was the unique novel CNV shared by the twins, confirming the involvement of CNTNAP3 gene in TGCTs development. Although similar CNV profiles were shared by both the peripheral blood and tumor samples of the twins, tumor-specific CNV loci were identified for seminoma and non-seminomatous tumors. These findings suggest the presence of de novo germline structural alterations and TGCT predisposition.
authors.affiliation: Neogene Laboratory, CIPE, A. C. Camargo Cancer Center, São Paulo, Brazil. sara_martorelli@yahoo.com.brl.
authors.forename: Sara Martoreli
authors.initials: SM
authors.lastname: Silveira
authors.affiliation: Department of Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil. iwcunha@accamargo.org.br.
authors.forename: Isabela Werneck
authors.initials: IW
authors.lastname: da Cunha
authors.affiliation: Institute of Mathematics and Statistics, Inter-Institutional Program on Bioinformatics, USP, São Paulo, Brazil. fmarchibr@hotmail.com.
authors.forename: Fabio Albuquerque
authors.initials: FA
authors.lastname: Marchi
authors.affiliation: Neogene Laboratory, CIPE, A. C. Camargo Cancer Center, São Paulo, Brazil. ariane.b@ig.com.br.
authors.forename: Ariane Fidelis
authors.initials: AF
authors.lastname: Busso
authors.affiliation: Nucleus of Sarcoma, Department of Pelvic Surgery, A.C. Camargo Cancer Center, São Paulo, Brazil. ademar-lopes@uol.com.br.
authors.forename: Ademar
authors.initials: A
authors.lastname: Lopes
authors.affiliation: Neogene Laboratory, CIPE, A. C. Camargo Cancer Center, São Paulo, Brazil. silvia.rogatto@cipe.accamargo.org.br.|Department of Urology, Faculty of Medicine, UNESP, Botucatu, São Paulo, Brazil. silvia.rogatto@cipe.accamargo.org.br.
authors.forename: Silvia Regina
authors.initials: SR
authors.lastname: Rogatto
mesh_terms: D020869:Gene Expression Profiling / Q000379:methods; D005820:Genetic Testing / Q000379:methods*; D023281:Genomics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009373:Neoplasms, Germ Cell and Embryonal / Q000175:diagnosis* / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D013736:Testicular Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics*; D055815:Young Adult
chemical_list: C464567:CNTNAP3 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins