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Molecular Heterogeneity and Early Metastatic Clone Selection in Testicular Germ Cell Cancer Development
by
Ronald Van Marion
, Stoop, Hans
, Gillis, Ad Jm
, Lambert Cj Dorssers
, Nieboer, Marleen M
, Job Van Riet
, J Wolter Oosterhuis
, Leendert Hj Looijenga
, Harmen Jg Van De Werken
, De Ridder, Jeroen
in
BRCA1 protein
/ BRCA2 protein
/ Breast cancer
/ Cancer Biology
/ Cancer therapies
/ Copy number
/ Embryos
/ Gene duplication
/ Genomes
/ Malignancy
/ Metastases
/ Metastasis
/ Stem cells
/ Testes
/ Tumorigenesis
2018
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Molecular Heterogeneity and Early Metastatic Clone Selection in Testicular Germ Cell Cancer Development
by
Ronald Van Marion
, Stoop, Hans
, Gillis, Ad Jm
, Lambert Cj Dorssers
, Nieboer, Marleen M
, Job Van Riet
, J Wolter Oosterhuis
, Leendert Hj Looijenga
, Harmen Jg Van De Werken
, De Ridder, Jeroen
in
BRCA1 protein
/ BRCA2 protein
/ Breast cancer
/ Cancer Biology
/ Cancer therapies
/ Copy number
/ Embryos
/ Gene duplication
/ Genomes
/ Malignancy
/ Metastases
/ Metastasis
/ Stem cells
/ Testes
/ Tumorigenesis
2018
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Molecular Heterogeneity and Early Metastatic Clone Selection in Testicular Germ Cell Cancer Development
by
Ronald Van Marion
, Stoop, Hans
, Gillis, Ad Jm
, Lambert Cj Dorssers
, Nieboer, Marleen M
, Job Van Riet
, J Wolter Oosterhuis
, Leendert Hj Looijenga
, Harmen Jg Van De Werken
, De Ridder, Jeroen
in
BRCA1 protein
/ BRCA2 protein
/ Breast cancer
/ Cancer Biology
/ Cancer therapies
/ Copy number
/ Embryos
/ Gene duplication
/ Genomes
/ Malignancy
/ Metastases
/ Metastasis
/ Stem cells
/ Testes
/ Tumorigenesis
2018
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Molecular Heterogeneity and Early Metastatic Clone Selection in Testicular Germ Cell Cancer Development
Paper
Molecular Heterogeneity and Early Metastatic Clone Selection in Testicular Germ Cell Cancer Development
2018
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Overview
Background: Testicular germ cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an embryonic germ cell. This study determines intratumor heterogeneity to unravel tumor progression from initiation till metastasis. Methods: In total 42 purified samples of four treatment-resistant nonseminomatous TGCC (NS) were investigated, including the precursor germ cell neoplasia in situ (GCNIS) and metastatic specimens, using whole genome- and targeted sequencing. Their evolution was reconstructed. Results: Intratumor molecular heterogeneity did not correspond to the supposed primary tumor histological evolution. Metastases after systemic treatment could be derived from cancer stem cells not identified in the primary cancer. GCNIS mostly lacked the molecular marks of the primary NS and comprised dominant clones that failed to progress. A BRCA-like mutational signature was observed without evidence for direct involvement of BRCA1 and BRCA2 genes. Conclusions: Our data strongly support the hypothesis that NS is initiated by whole genome duplication, followed by chromosome copy number alterations in the cancer stem cell population, and accumulation of low numbers of somatic mutations. These observations of heterogeneity at all stages of tumorigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS. Footnotes * Text, Figure 2, Figure 3, Supplemental Figures and Supplemental Tables S7 and S8 were updated
Publisher
Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
Subject
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