TY - JOUR
T1 - Molecular heterogeneity and early metastatic clone selection in testicular germ cell cancer development
AU - Dorssers, Lambert C J
AU - Gillis, Ad J M
AU - Stoop, Hans
AU - van Marion, Ronald
AU - Nieboer, Marleen M
AU - van Riet, Job
AU - van de Werken, Harmen J G
AU - Oosterhuis, J Wolter
AU - de Ridder, Jeroen
AU - Looijenga, Leendert H J
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/2
Y1 - 2019/2
N2 - 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 intratumour heterogeneity to unravel tumour progression from initiation until metastasis.METHODS: In total, 42 purified samples of four treatment-resistant nonseminomatous (NS) TGCC 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: Intratumour molecular heterogeneity did not correspond to the supposed primary tumour 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, even in therapy-resistant cases. These observations of heterogeneity at all stages of tumourigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS.
AB - 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 intratumour heterogeneity to unravel tumour progression from initiation until metastasis.METHODS: In total, 42 purified samples of four treatment-resistant nonseminomatous (NS) TGCC 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: Intratumour molecular heterogeneity did not correspond to the supposed primary tumour 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, even in therapy-resistant cases. These observations of heterogeneity at all stages of tumourigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS.
KW - Evolution, Molecular
KW - Genes, BRCA1
KW - Genes, BRCA2
KW - Humans
KW - Loss of Heterozygosity
KW - Male
KW - Mutation
KW - Neoplasm Metastasis
KW - Neoplasms, Germ Cell and Embryonal/genetics
KW - Testicular Neoplasms/genetics
KW - Whole Genome Sequencing
UR - http://www.scopus.com/inward/record.url?scp=85061336888&partnerID=8YFLogxK
U2 - 10.1038/s41416-019-0381-1
DO - 10.1038/s41416-019-0381-1
M3 - Article
C2 - 30739914
SN - 1532-1827
VL - 120
SP - 444
EP - 452
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 4
ER -