title: High-resolution telomere fluorescence in situ hybridization reveals intriguing anomalies in germ cell tumors.
abstract: Testicular germ cell tumor (TGCT) is the most common malignancy of young men. Most patients are completely cured, which distinguishes these from most other malignancies. Orchiectomy specimens (n=76) were evaluated using high-resolution (single-cell discriminative) telomere-specific fluorescence in situ hybridization (FISH) with simultaneous Oct4 immunofluorescence to describe telomere length phenotype in TGCT neoplastic cells. For the first time, the TGCT precursor lesion, germ cell neoplasia in situ (GCNIS) is also evaluated in depth. The intensity of the signals from cancerous cells was compared to the same patient's reference cells-namely, healthy germ cells (defined as "medium" length) and interstitial/somatic cells (defined as "short" telomere length). We observed short telomeres in most GCNIS and pure seminomas (P=.006 and P=.0005, respectively). In contrast, nonseminomas displayed longer telomeres. Lesion-specific telomere lengths were documented in mixed tumor cases. Embryonal carcinoma (EC) demonstrated the longest telomeres. A fraction of EC displays the telomerase-independent alternative lengthening of telomeres (ALT) phenotype (24% of cases). Loss of ATRX or DAXX nuclear expression was strongly associated with ALT; however, nuclear expression of both proteins was retained in half of ALT-positive ECs. The particular distribution of telomere lengths among TGCT and GCNIS precursors implicate telomeres anomalies in pathogenesis. These results may advise management decisions as well.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Mohammed Talha
authors.initials: MT
authors.lastname: Shekhani
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: John R
authors.initials: JR
authors.lastname: Barber
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Stephania M
authors.initials: SM
authors.lastname: Bezerra
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Heaphy
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Nilda Diana
authors.initials: ND
authors.lastname: Gonzalez Roibon
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Diana
authors.initials: D
authors.lastname: Taheri
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Leonardo O
authors.initials: LO
authors.lastname: Reis
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Gunes
authors.initials: G
authors.lastname: Guner
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Joshu
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Urology, James Buchanan Brady Urological Institute at Johns Hopkins, Baltimore, MD.
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Urology, James Buchanan Brady Urological Institute at Johns Hopkins, Baltimore, MD. Electronic address: Alan.meeker@gmail.com.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Meeker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002278:Carcinoma in Situ / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000032:analysis; D005455:Fluorescent Antibody Technique; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D018832:Molecular Chaperones; D009373:Neoplasms, Germ Cell and Embryonal / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D009687:Nuclear Proteins / Q000032:analysis; D050814:Octamer Transcription Factor-3 / Q000032:analysis; D018239:Seminoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016615:Telomere / Q000737:chemistry / Q000235:genetics*; D059505:Telomere Homeostasis; D059506:Telomere Shortening; D013736:Testicular Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000075924:X-linked Nuclear Protein; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: Embryonal carcinoma; FISH, alternative lengthening of telomeres (ALT); Germ cell neoplasia in situ (GCNIS); Oct4; Seminoma; Telomere; Testicular germ cell tumor (TGCT)