Exome sequencing of bilateral testicular germ cell tumors suggests independent development lineages.
Intratubular germ cell neoplasia, the precursor of testicular germ cell tumors (TGCTs), is hypothesized to arise during embryogenesis from developmentally arrested primordial germ cells (PGCs) or gonocytes. In early embryonal life, the PGCs migrate from the yolk sac to the dorsal body wall where the cell population separates before colonizing the genital ridges. However, whether the malignant transformation takes place before or after this separation is controversial. We have explored the somatic exome-wide mutational spectra of bilateral TGCT to provide novel insight into the in utero critical time frame of malignant transformation and TGCT pathogenesis. Exome sequencing was performed in five patients with bilateral TGCT (eight tumors), of these three patients in whom both tumors were available (six tumors) and two patients each with only one available tumor (two tumors). Selected loci were explored by Sanger sequencing in 71 patients with bilateral TGCT. From the exome-wide mutational spectra, no identical mutations in any of the three bilateral tumor pairs were identified. Exome sequencing of all eight tumors revealed 87 somatic non-synonymous mutations (median 10 per tumor; range 5-21), some in already known cancer genes such as CIITA, NEB, platelet-derived growth factor receptor α (PDGFRA), and WHSC1. SUPT6H was found recurrently mutated in two tumors. We suggest independent development lineages of bilateral TGCT. Thus, malignant transformation into intratubular germ cell neoplasia is likely to occur after the migration of PGCs. We reveal possible drivers of TGCT pathogenesis, such as mutated PDGFRA, potentially with therapeutic implications for TGCT patients.
Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Sigmund
S
Brabrand
Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Bjarne
B
Johannessen
Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Ulrika
U
Axcrona
Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Sigrid M
SM
Kraggerud
Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Kaja G
KG
Berg
Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Anne C
AC
Bakken
Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Jarle
J
Bruun
Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Sophie D
SD
Fosså
Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Ragnhild A
RA
Lothe
Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Gustav
G
Lehne
Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Center for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: rolf.i.skotheim@rr-research.no.
Rolf I
RI
Skotheim
D000328:Adult; D019070:Cell Lineage; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction / Q000379:methods; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics; D017422:Sequence Analysis, DNA; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology
D009363:Neoplasm Proteins; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor