Exome Sequencing of Bilateral Testicular Germ Cell Tumors Suggests Independent Development Lineages

Adult Male 0301 basic medicine 0303 health sciences DNA Mutational Analysis Neoplasms. Tumors. Oncology. Including cancer and carcinogens Sequence Analysis, DNA Neoplasms, Germ Cell and Embryonal Polymerase Chain Reaction Article Neoplasm Proteins 3. Good health Proto-Oncogene Proteins c-kit 03 medical and health sciences Testicular Neoplasms Humans Cell Lineage Exome Receptors, Platelet-Derived Growth Factor RC254-282 Germ-Line Mutation
DOI: 10.1016/j.neo.2014.12.005 Publication Date: 2015-03-03T22:03:01Z
ABSTRACT
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.
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