title: Copy number variations ofE2F1: a new genetic risk factor for testicular cancer.
abstract: Testicular germ cell tumor (TGCT) is one of the most heritable forms of cancer. In last years, many evidence suggested that constitutional genetic factors, mainly single nucleotide polymorphisms, can increase its risk. However, the possible contribution of copy number variations (CNVs) in TGCT susceptibility has not been substantially addressed. Indeed, an increasing number of studies have focused on the effect of CNVs on gene expression and on the role of these structural genetic variations as risk factors for different forms of cancer. E2F1 is a transcription factor that plays an important role in regulating cell growth, differentiation, apoptosis and response to DNA damage. Therefore, deficiency or overexpression of this protein might significantly influence fundamental biological processes involved in cancer development and progression, including TGCT. We analyzedE2F1CNVs in 261 cases with TGCT and 165 controls. We found no CNVs in controls, but 17/261 (6.5%) cases showed duplications inE2F1Blot analysis demonstrated higher E2F1 expression in testicular samples of TGCT cases with three copies of the gene. Furthermore, we observed higher phosphorylation of Akt and mTOR in samples withE2F1duplication. Interestingly, normal, non-tumoral testicular tissue in patient withE2F1duplication showed lower expression of E2F1 and lower AKT/mTOR phosphorylation with respect to adjacent tumor tissue. Furthermore, increased expression of E2F1 obtainedin vitroin NTERA-2 testicular cell line induced increased AKT/mTOR phosphorylation. This study suggests for the first time an involvement ofE2F1CNVs in TGCT susceptibility and supports previous preliminary data on the importance of AKT/mTOR signaling pathway in this cancer.
authors.affiliation: Department of MedicineDIMED University of Padua, Padua, Italy.
authors.forename: Maria Santa
authors.initials: MS
authors.lastname: Rocca
authors.affiliation: Department of MedicineDIMED University of Padua, Padua, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Nisio
authors.affiliation: Department of MedicineDIMED University of Padua, Padua, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Marchiori
authors.affiliation: Department of MedicineDIMED University of Padua, Padua, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ghezzi
authors.affiliation: Department of MedicineDIMED University of Padua, Padua, Italy.|Familial Tumor UnitVeneto Institute of Oncology IOV-IRCCS, Padua, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.affiliation: Department of MedicineDIMED University of Padua, Padua, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Foresta
authors.affiliation: Department of MedicineDIMED University of Padua, Padua, Italy alberto.ferlin@unipd.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferlin
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012307:Risk Factors; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: E2F1; copy number variations; non-seminoma; testicular cancer